Biological Substrates of Human Sexuality

Substrates^
edited by Janet Shibley Hyde
AMERICAN PSYCHOLOGICAL ASSOCIATION

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Biological substrates of human sexuality / edited by Janet Shibley Hyde.— 1st ed.
p. cm.
Includes bibliographical references and index.
ISBN 1-59147-250-4
1. Sex (Biology) I. Hyde, Janet Shibley.
QP251.B5626 2005
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First Edition
CONTENTS
Contributors vii
Acknowledgments ix.
Chapter 1. Introduction: The Role of Modern Neuroscience in

Sexuality Research 3
Janet Shibley Hyde
Chapter 2. The Genetics of Sexual Orientation 9
Janet Shibley Hyde
Chapter 3. The Role of Hypothalamus and Endocrine
System in Sexuality 21
Dick F. Swaab
Chapter 4- The Central Control and Pharmacological
Modulation of Sexual Function 75
Kevin E. McKenna
Chapter 5. Brain Activity Imaging During Sexual Response in
Women With Spinal Cord Injury 109
Barry R. Komisaruk and Beverly Whippk
Chapter 6. Neuroanatomical and Neurotransmitter Dysfunction
and Compulsive Sexual Behavior 147
Eh' Coleman
Chapter 7. Synthesis: Overarching Themes and Future
Directions for Research 171
Janet Shibley Hyde and Beverly Whipple
v
Author Index 179
Subject Index 195
About the Editor 207
vi CONTENTS
CONTRIBUTORS
Eli Coleman, University of Minnesota Medical School, Minneapolis

Barry R. Komisaruk, Rutgers University, Medford, NJ
Janet Shibley Hyde, University of Wisconsin—Madison
Kevin E. McKenna, Northwestern University, Chicago, IL
Dick F. Swaab, Netherlands Institute for Brain Research, Amsterdam,
the Netherlands
Beverly Whipple, Rutgers University, Medford, NJ
ACKNOWLEDGMENTS
This volume began with a conference on the biological substrates of

human sexuality at the beginning of a meeting of the Society for the
Scientific Study of Sexuality in June 2002. We are grateful to those who
provided funding for the conference and the writing of these chapters. The
Science Directorate of the American Psychological Association supported
the conference in the form of funds for graduate students to attend the
conference, providing them with exciting opportunities to interact with the
premier scientists in the field. Funding for speakers was provided by the
National Institute of Child Health and Human Development and by the
Sexuality Research Program of the Social Science Research Council (Diane
DiMauro, program officer).
IX
Biological Substrates of Human Sexuality
INTRODUCTION: THE ROLE OF
MODERN NEUROSCIENCE IN
SEXUALITY RESEARCH
JANET SHIBLEY HYDE
The past decade has witnessed an explosion of neuroscience research

on sexuality. This research has been driven by three forces: the quest of
drug companies for Viagra and even better successors; technological advances
in numerous areas, including functional magnetic resonance imaging (fMRI)
technology; and advances in neuroscience techniques in both animal and
human postmortem research. The result is that a tremendous amount more
is known today about the biological substrates of human sexuality than 10
years ago.
I use the terms neuroscience and biological substrates in their broadest
sense here, to include central and peripheral neural pathways, neurotransmit-
ters, the endocrine system, genetic blueprints, and interactions among all
these systems. The emphasis on biological substrates is not intended to slight
the enormous cultural, interpersonal, and individual life history influences on
sexuality, which are well documented elsewhere (e.g., Adkins-Regan, 2002;
Frayser, 1985, 1994; Gregersen, 1996; Herdt, 1984, 1997; Wyatt, 1997). I
seek only to focus on a specific piece of the puzzle, namely the biological
substrates.
This volume is above all integrative. It integrates research on humans
and animals; research on males and females; research using vastly different
methodologies including twin studies, fMRI, viral tracers to identify neuro-
anatomy, and experimental pharmacology; and research at multiple levels
of analysis from the molecular (McKenna's chapter on pharmacology) to
the familial (Hyde's chapter on family resemblance for sexual orientation).
It integrates a fascinating array of aspects of sexuality, including sexual
orientation, orgasm, erectile dysfunction, the sexual functioning of women
with spinal cord injury, and compulsive sexual behavior. The authors repre-
sent a variety of disciplines, including psychology, physiology, neuroscience,
urology, and nursing.
This book will be useful to many sectors of the community of psycholo-
gists. Practitioners increasingly need to understand the biological substrates
of both male and female sexual functioning and dysfunction; for example,
they need to know what sorts of clients might benefit from Viagra. Those
who teach human sexuality, behavioral neuroscience, or biopsychology in
colleges and universities will find in this volume much-needed information
for updating their teaching. And certainly researchers in sexuality and
related fields will appreciate the cutting-edge reviews found in the chapters
that follow.
This book integrates multiple levels of analysis, ranging from the most
basic to the most complex. The book begins with genes, the basic biological
blueprints, and Hyde's chapter on the genetics of sexual orientation. The
next chapter moves to the cellular level, focusing on the hypothalamus, a
region of the brain that has been implicated particularly in sexual behavior
and identity. Swaab's chapter reviews research on the important regions of
the human hypothalamus and their connections to the sex hormone system,
also discussing data from animal research. McKenna focuses on the central
nervous system, synthesizing research that has identified the pathways in
the brain and spinal cord, and the neurotransmitters that are involved
in sexual function and dysfunction. Komisaruk and Whipple review their
pathbreaking research using fMRI and positron emissions tomography (PET)
scans to understand how women with complete spinal cord injury can
nonetheless feel genital stimulation and experience orgasm. Finally, we
move to the level of clinical applications, with Coleman's chapter on com-
pulsive sexual behavior and the neural dysregulation that may underlie it.
One overarching theme is prominent across chapters. Sexuality is
multifaceted and complex, even in the rat. In the male rat, for example,
mounting, intromission with erection, and ejaculation are all distinct pro-
cesses with somewhat different neural control. In humans, sexual orientation
may be defined by behavior, attraction, or identity, and individuals may be
discordant from one aspect to another. It is unfortunate that some recent
trends in the field ignore these distinctions. For example, some speak of
4 JANET SHIBLEY HYDE

"female sexual dysfunction" as if it were a single diagnostic category, masking
the multiplicity of sexual dysfunctions and dissatisfactions that women can
experience. Each of those dysfunctions may have distinct biological sub-
strates and sources of learning through the environment and experience. The
chapters that follow give ample recognition to the complexity of sexuality.
In chapter 2, Hyde reviews the evidence on whether there is a genetic
basis for sexual orientation. Much of the evidence comes from studies of
identical (monozygotic or MZ) twins compared with fraternal (dizygotic or
DZ) twins and their concordance for homosexuality—or, more precisely,
nonheterosexual orientation, including both homosexuality and bisexuality.
Sufficient studies using strong methods now exist to support the conclusion
that nonheterosexual orientation is moderately heritable. Other researchers
have advanced the hypothesis that homosexuality in some men is influenced
by a gene on the X chromosome, called Xq28. The replicability of these
findings is somewhat ambiguous. Results of the first genomewide scan for
male sexual orientation, published in 2005, are included. Hyde also reviews
genomic research with other species such as fruit flies, which has identified
specific genes controlling specific aspects of sexual behavior such as the
courtship ritual. Finally, Hyde considers the ethical issues that will arise if
specific genes influencing homosexual orientation are identified.
Swaab has conducted a long and distinguished program of research on
the hypothalamus and endocrine system and reports on this and related research
in chapter 3. Patterns of sex differences and control of sexual behavior have
been identified in certain regions of the hypothalamus. For example, the
sexually dimorphic nucleus of the preoptic area (SDN-POA, also known
as the interstitial nucleus of the anterior hypothalamus, or INAH-1 in
humans) shows marked anatomical differences between males and females
across numerous species. Lesions of the preoptic area eliminate mounting,
intromission, and ejaculation in male rats. This region also contains an
abundance of both androgen receptors and estrogen receptors and contri-
butes to the regulation of circulating levels of these sex hormones throughout
the body. Swaab's discussion ranges over questions of sexual orientation
and transsexualism and the possible involvement of the hypothalamus in
these patterns of behavior and identity. A glossary beginning on p. 73 makes
this technical chapter more accessible. Clearly the hypothalamus is one of
the brain's real hot spots for sexual functioning.
In chapter 4, McKenna considers the role of the central nervous system—
brain and spinal cord—and neurotransmitters, focusing particularly on
mechanisms influencing erection in males. McKenna has been a major
contributor to the basic science that supported the development of prescrip-
tion drugs to treat erectile dysfunction. Viagra acts peripherally, facilitating
vasocongestion in the penis. Strategies for successor drugs are capitalizing
on central mechanisms as well. McKenna reviews new discoveries about
INTRODUCTION
the neuroanatomy of sexual response, focusing on sites such as reflex centers
in the spinal cord, and the inhibitory role of the brainstem (medulla and
pons). In his consideration of the pharmacology of sexual response, McKenna
focuses particularly on the neurotransmitter serotonin, which generally has
an inhibitory effect on sexual functioning. This leads to the unfortunate
result that many drugs prescribed for the treatment of depression and de-
signed to raise serotonin levels—particularly the selective serotonin reup-
take inhibitors (SSRIs)—have marked sexual dysfunctions as side effects.
McKenna considers several other neurotransmitters as well, including dopa-
mine, noradrenaline, oxytocin, and nitric oxide.
Given that brain and spinal cord mechanisms of sexual response (as
reviewed by McKenna) are well established, Komisaruk and Whipple begin
chapter 5 with a paradox: How could women with compkte spinal cord injury
feel genital stimulation and experience orgasm? For genital sensations to be
consciously perceived, they must travel from sensory neurons in the genitals,
to neurons in the spinal cord, and then to an ascending pathway through
the spinal cord that eventually registers in the cortex. How could women
whose spinal cords have been completely severed at a level above the point
where the sensory neurons join the spinal cord feel genital sensation when
the ascending pathway has been severed? Komisaruk and Whipple's path-
breaking research began by taking the reports of these women seriously
rather than dismissing them as "phantom" sensations. Through a remarkable
series of laboratory studies of these women, using fMRI and PET technolo-
gies, they have demonstrated an alternative sensory pathway involving the
Vagus nerve, which completely bypasses the spinal cord and projects directly
to the brain. Their imaging studies have also identified a region of the
hypothalamus that is activated during orgasm. Their findings have profound
implications for practitioners who may mistakenly tell their clients with
spinal cord injury that sex is a thing of the past for them. Komisaruk and
Whipple show how and why sexual response may still be possible in many
cases of spinal cord injury.
In chapter 6, Coleman addresses the issue of compulsive sexual behavior
(CSB, also called sexual addiction by some) and its substrates in neuroanat-
omy, hormones, and neurotransmitters. Coleman is arguably the nation's
expert on CSB and its treatment. He finds that the limbic system of the
brain is particularly implicated. Although findings regarding elevated levels
of testosterone in individuals with CSB are equivocal, there is substantial
evidence that antiandrogen treatments are effective. Posttraumatic stress
disorder and the associated neural consequences may be implicated in some
cases of people with CSB who were victims of childhood sexual abuse.
SSRIs and other antidepressants are effective in treating many cases of CSB.
In the final chapter, Hyde and Whipple synthesize the findings reported
in the previous chapters and identify five overarching themes: Biological
JANET SHIBLEY HYDE

substrates are developmental; sexuality is complex and multifaceted; certain
regions of the brain, particularly the hypothalamus, are clearly linked to
sexuality; the spinal cord plays a key role as well; and the biological substrates
consist of multiple, interlocking systems, including genes, the brain, and
the endocrine system. They conclude with suggestions about future directions
for research on the biological substrates of human sexuality.
The array of research displayed in these chapters is dazzling. It testifies
to the possibility of rapid scientific progress in understanding crucial areas
of human behavior such as sexuality. This research has flourished despite
societal taboos regarding sex research and opposition of some in the federal
government. We hope that readers will gain much from reading these
chapters.
REFERENCES
Adkins-Regan, E. (2002). Development of sexual partner preference in the zebra

finch: A socially monogamous, pair-bonding animal. Archives of Sexual Behavior,
31, 27-33.
Frayser, S. G. (1985). Varieties of sexual experience: An anthropological perspective on
human sexuality. New Haven, CT: Human Relations Area Files Press.
Frayser, S. G. (1994). Defining normal childhood sexuality: An anthropological
approach. Annual Review of Sex Research, 5, 173-217.
Gregersen, E. (1996). The world of human sexuality: Behaviors, customs, and beliefs.
New York: Irvington.
Herdt, G. H. (1984). Ritualized homosexuality in Melanesia. Berkeley: University of
California Press.
Herdt, G. H. (1997). Same sex, different cultures. Boulder, CO: Westview Press.
Wyatt, G. E. (1997). Stolen women: Reclaiming our sexuality, taking back our lives.
New York: Wiley.
INTRODUCTION 7
THE GENETICS OF
SEXUAL ORIENTATION
JANET SHIBLEY HYDE
We live in the era of the Human Genome Project, and genes are being
identified that control everything from full fruit development in strawberries
to breast cancer susceptibility in women (Marshall, 1999; Miki et al., 1994).
At the same time, this is an era in which issues of sexual orientation have
been placed front and center. In 2003 alone, an openly gay man, the Rev.
Gene Robinson, was confirmed as a bishop in the Episcopal Church, and
an amendment was proposed to the U.S. Constitution specifying that mar-
riage could occur only between a man and a woman. It is therefore not
surprising that the lay public, scientists, and practitioners should wonder
about the causes of sexual orientation and, specifically, whether there is a
genetic basis for sexual orientation.
In this chapter I review the evidence on genetic influence on sexual
orientation in humans, including evidence from twin and adoption studies,
as well as evidence from studies using animal models. (For earlier reviews,
see Bailey & Pillard, 1995; Mustanski, Chivers, & Bailey, 2002; Pillard &
Bailey, 1998.) I conclude with a consideration of the ethical issues that are
raised by this newly emerging science.
As we consider the evidence, an important methodological issue is the
measurement of sexual orientation. Alfred Kinsey championed a behavioral
9
definition captured in his famous 7'point rating scale in which 0 represented
a person all of whose sexual contacts were heterosexual, 3 represented equal
amounts of heterosexual and homosexual experience, and 6 represented all
same-gender sexual experience (Kinsey, Pomeroy, & Martin, 1948; Kinsey,
Pomeroy, Martin, &. Gebhard, 1953). Identity, fantasy, and attraction are
additional components of sexual orientation that contemporary researchers
consider. Sexual identity refers to one's own self-label as being heterosexual,
homosexual, bisexual, or other categories, such as queer. Identity typically
is measured categorically. Moreover, sexual identity can be notably discor-
dant from sexual behavior (Lever, Kanouse, & Rogers, 1992). For example,
a woman may self-label as bisexual even though all her sexual experiences
have been with men. Likewise, a woman may have experienced sexual
attraction to other women but never acted on it. The well-known National
Health and Social Life Survey, for example, asked respondents about behav-
ior, identity, and attraction (Laumann, Gagnon, Michael, & Michaels,
1994). The measurement of sexual orientation is not standardized in genetic
research, so differences in measurement may account for variations in out-
comes across studies.
EVIDENCE FROM TWIN AND ADOPTION STUDIES
Behavior geneticists who study humans cannot perform the experimen-

tal manipulations that are possible when studying nonhumans. Therefore,
they capitalize on a number of "natural" experiments, such as identical twins.
Monozygotic (MZ), or identical, twins are two individuals with identical
genotypes. The question, then, is whether they are concordant or discordant
for the trait under study. In this paradigm, probands are identified who
possess the trait under investigation—in this case, who are gay or lesbian—
and are also a member of an MZ twin pair. The other member of the pair
is then located and the sexual orientation of that individual is ascertained.
If the other member of the pair also is gay, then the pair is said to be
concordant. If not, then the pair is discordant. Generally results from these
studies are reported as concordance rates—in this case, the percentage of
the twin pairs in which both members are gay.
The study of identical twins by itself is limited because the twins not
only share all their genes but also grew up in the same environment, so
concordance might be due either to genetic factors or to environmental
ones. To address this limitation, human behavior geneticists have used a
variety of methods, including studies of MZ twins reared apart. For a relatively
uncommon trait such as homosexuality, studies of identical twins reared
apart are generally not feasible; one would have to locate people who were
gay, who were members of an identical twin pair, and who were separated

and reared apart from the first year of life. The resulting sample size would
be tiny and would not permit statistical analysis.
The alternative, more feasible design is to compare concordance rates
for identical twins with those from dizygotic (DZ) or nonidentical, fraternal
twins. DZ twins are two individuals born at the same time who are not
genetically identical but rather are as similar as siblings. Like identical twins
reared together, DZ twins share a common environment. Therefore, any
difference in concordance rates between MZ and DZ twins should be due
to the greater genetic similarity of MZ twins.
Yet another design involves the study of adoptive siblings. They are
genetically unrelated, but they are reared in the same environment. High
concordance rates would testify to the importance of environment.
Early genetic studies of homosexuality by Kallmann (1952a, 1952b)
indicated a strong genetic influence. Kallmann found perfect concordance
for homosexuality among all the MZ pairs he studied, all of whom were
men, and nonsignificant concordance among the DZ pairs. The methods
of the study were later criticized, though, and one study failed to replicate
it (Heston & Shields, 1968). For a time, the hypothesis of genetic influence
on sexual orientation was discarded.
The modern era of behavior-genetic research on sexual orientation
was ushered in by a series of studies by Bailey and colleagues. In the first
study, they identified 56 gay men who were members of an MZ twin pair
(Bailey & Pillard, 1991). When the identical twin brothers were located,
the concordance rate proved to be 52%. In the comparison sample of 54
gay men who were members of a DZ twin pair, the concordance rate was
only 22%. That the MZ twins were considerably more likely to be concordant
for homosexuality is taken as evidence of genetic influence on sexual orienta-
tion. Nonetheless, the concordance rate for the MZ pairs was not 100%,
indicating that genes do not completely control sexual orientation. Measure-
ment of sexual orientation of the probands was self-definition; recruiting
advertisements asked for volunteers who were gay or bisexual who had a
twin. Sexual orientation was then confirmed during an interview using the
Kinsey rating scale for both fantasy and behavior.
In this same study, Bailey and Pillard (1991) also located gay men
who were adopted or had an adopted sibling. The concordance rate for
these genetically unrelated pairs was 11%—far below the rate for MZ or
DZ twins, and not much higher than one would expect at random, given
that roughly 6% to 8% of men in the United States are gay (Hyde &
DeLamater, 2003; Laumann et al., 1994).
In a companion study, Bailey, Pillard, Neale, and Agyei (1993) repeated
the design with lesbians as probands. The concordance rates were 48% for
MZ twin pairs (based on 71 pairs), 16% for DZ twin pairs (based on 37
pairs), and 6% for adoptive sisters (based on 35 pairs). That is, the results
THE GENETICS OF SEXUAL ORIENTATION 11

were very similar to those for gay men and indicated some genetic influence
on women's sexual orientation, but not complete genetic control of sex-
ual orientation.
Two other studies using the same design comparing MZ and DZ pairs
have also appeared, although they have smaller sample sizes and combined
male and female pairs. Whitam, Diamond, and Martin (1993) found a 66%
concordance rate for MZ pairs and 30% for DZ pairs. They assessed sexual
orientation using respondents' self-ratings of behavior on the 7-point Kinsey
scale. King and McDonald (1992) found a concordance rate of 25% for MZ
and 12% for DZ pairs, pooling male pairs and female pairs. Measurement
was weak because cotwins were not contacted; the researchers simply ac-
cepted the reports of probands about their own and their twin's orientation.
The design used in these studies, although illuminating, contains some
embedded biases. In particular, when probands are recruited, concordant
pairs are considerably more likely to be identified than discordant pairs. If
recruiting signs are placed in gay bars and newsletters for gays, either member
of concordant pairs may see the ad and respond to it, whereas in discordant
pairs, only one member of the pair can respond.
A design that corrects for this bias is the registry study. Australia, for
example, has a twin registry, a national database containing roughly 25,000
twin pairs in Australia (Bailey, Dunne, & Martin, 2000). Registration is
voluntary, which may introduce some bias, but for the purposes of sexual
orientation research, the important point is that it is a general twin registry.
That is, people were not recruited on the basis of sexual orientation or any
other specific characteristic. Bailey and colleagues capitalized on this registry
to identify nonheterosexual twins, that is, twins who scored >2 on the
Kinsey scale. For men, the concordance rate for MZ twins was 20%, compared
with 0% for DZ twins. For women, concordance was 24% for MZ twin pairs
and 10.5% for DZ twins. The results are again consistent with a genetic
model of sexual orientation. As expected on the basis of methodological
considerations, the concordance rate was lower than that found in the
earlier studies that used different recruiting methods. The superiority of the
twin registry method means that the 20% to 24% concordance rate is likely
to be more accurate.
A second registry study used the Minnesota Twin Registry and con-
tacted never-married twins on the basis of the idea that they were most
likely to be gay (Hershberger, 1997). That assumption, of course, ignores
people who are bisexual and heterosexually married. Sexual orientation was
assessed with distinct variables focusing on attraction, behavior, and identity.
Concordance rates were higher for MZ lesbians (0.55 for attraction, 0.50
for behavior, and 0.52 for identity, based on 101 pairs) than for MZ gay
men (0.23, 0.14, and 0.16, respectively, based on 76 pairs).
]2 JANET SHIBLEY HYDE

A U.S. national sample of twin pairs, again not recruited on the basis
of sexual orientation, also provides evidence of genetic influence. The sample
was drawn from the MacArthur Foundation's Midlife Development in the
United States (MIDUS) survey. Kendler, Thornton, Oilman, and Kessler
(2000) found a concordance rate for nonheterosexual orientation of 31.6%
for MZ pairs (males and females combined, 19 pairs), compared with a
13.3% concordance for DZ twins (24 pairs). These results are consistent
with those of Bailey et al. (2000) with the Australian twin registry. The
MIDUS survey measured sexual orientation with a single item: "How
would you describe your sexual orientation? Would you say you are
heterosexual (sexually attracted only to the opposite sex), homosexual
(sexually attracted only to your own sex), or bisexual (sexually attracted
to both men and women)?" This item assesses a combination of identity
and attraction, not behavior. In statistical analyses, the second and third
response alternatives were combined so that two categories remained:
heterosexual and nonheterosexual.
TWIN STUDIES: THE EQUAL ENVIRONMENTS ASSUMPTION
In twin studies, differences between concordance rates for MZ versus

DZ twins are attributed to the greater genetic similarity of the MZ twin
pairs. This logic relies on the assumption that DZ twins' environments are
similar to each other to the same degree that MZ twins' environments are
similar (Bailey &. Pillard, 1995). The objection that has been raised is
that parents might treat MZ twins more similarly than they do DZ twins.
(Generally the sample of DZ twins is limited to same-sex pairs so that gender
differences in behavior or in parents' treatment do not cloud the results;
all MZ pairs, of course, are same-sex.) Empirical tests of the assumption, in
the context of sexual orientation research, have generally supported the
equal environments assumption. Bailey et al. (2000) found that concordant
MZ twins were no more similar than discordant MZ twins on an index of
childhood experiences. Kendler et al. (2000) found that twin resemblance
for sexual orientation was not significantly predicted by measures of similarity
of childhood environments.
OTHER FAMILIAL STUDIES
Other behavior-genetic designs involve assessing resemblance for

other family relationships such as siblings. In one study, 6.4% of the sisters
of lesbians were themselves nonheterosexual, compared with 0%

nonheterosexuals among sisters of heterosexual women (Bailey & Bell,
1993). In that same study, 9% of the brothers of homosexual men were
themselves nonheterosexual. In another study, 15.4% of sisters of lesbian
probands rated themselves homosexual or bisexual, as did 6.1% of brothers
of male homosexual probands (Bailey & Benishay, 1993). These rates were
higher than the rates of homosexuality reported by siblings of heterosexual
probands: 3.5% for women and 0% for men. The results of these studies
are also consistent with the hypothesis that sexual orientation is heritable,
although the twin designs provide somewhat more persuasive evidence.
THE SINGLE-GENE HYPOTHESIS
Most behaviors that are genetically influenced, particularly those that

are continuous traits with normal distributions, are thought to be polygenic,
that is, influenced by multiple genes at multiple loci. Although the twin
studies reviewed above are silent on this issue, it seems likely that the high
but uneven concordance rates in MZ twins reflect polygenic influence.
In contrast to polygenic models are single-gene models, with the as-
sumption that a single gene at a single locus can influence complex behavior.
An example of this model is the much-publicized work of Hamer, Hu,
Magnuson, Hu, and Pattatucci (1993). They used pedigree and linkage
analyses to study the families of 114 homosexual men. Pedigree analysis refers
to tracing the presence of a trait among relatives. Linkage analysis is done
with samples of DNA from relatives and refers to determining whether the
same alleles are present in a certain chromosome region (in this case, a
region of the X chromosome) for relatives who are concordant for the trait.
Men receive their X chromosome from their mother, so if a gene on the X
chromosome produces a homosexual orientation, then rates of homosexuality
should be elevated among men on the gay proband's mother's side of the
family but not the father's side. The results indicated increased rates of
homosexual orientation in maternal uncles of the probands but not in
paternal uncles, suggesting transmission by a gene on the X chromosome.
Linkage studies indicated inheritance through a gene on a particular region
of the X chromosome, labeled Xq28.
A later study confirmed these results for Xq28 for homosexual orienta-
tion in males but not in females (Hu et al., 1995). Another study by an
independent group, however, failed to replicate the findings for Xq28 (Rice,
Anderson, Risch, & Ebers, 1999). The reasons for the inconsistency of
findings is not entirely clear but may have to do with the protocol used for
excluding cases. For example, Hamer et al. (1993) excluded families if the
father was gay, whereas Rice and colleagues did not. Conclusions must
remain tentative until there is further evidence of replication.
14 JANET SH1BLEY HYDE

A major breakthrough came in 2005 with the first full genome scan
for sexual orientation in men (Mustanski, DuPree, Nievergelt, Bocklandt,
Schork, & Hamer, 2005). The sample included 456 individuals from 146
distinct families, all of which had at least two gay brothers. Mustanski and
colleagues found evidence for genetic transmission by regions on chromo-
somes 7, 8, and 10. The strongest evidence was for chromosome 7, with
equal contributions from maternal and paternal alleles. This region of chro-
mosome 7 contains the gene for vasoactive intestinal peptide (VIP) receptor
type 2 (VIPR2). In studies with mice, VIPR2 has been demonstrated to be
essential for the development of the suprachiasmatic nucleus (SCN) of
the hypothalamus. The SCN has previously been associated with sexual
orientation in humans (Swaab, chap. 3 this volume). Therefore, the evidence
of genetic linkage on that region of chromosome 7 is quite intriguing.
HOMOSEXUALITIES
A number of experts have noted that gay men do not form a homo-
geneous category, nor do lesbians (e.g., Bell & Weinberg, 1978). This
concept is represented by the use of the term homosexualities rather than
homosexuality. Kinsey's 7-point scale assessing various mixtures of heterosex-
ual and homosexual experience in individuals' histories is one recognition
of this variability (Kinsey et al, 1948, 1953).
The concept that homosexuals form a heterogeneous category, or that
there are multiple subtypes of homosexuals, must be linked to the genetic
research. It may be that one subtype of gay men has their orientation because
of a gene on the X chromosome, another subtype is the result of poly genie
influence, and yet another subtype is the result of prenatal events. Blanch-
ard's group, for example, has found repeatedly that, compared with heterosex-
ual men, gay men are more likely to have a late birth order and to have
more older brothers but not older sisters (Blanchard & Bogaert, 1996;
Blanchard & Klassen, 1997). They attribute this phenomenon to the forma-
tion of H-Y antigen by the mother with each pregnancy with a boy; H-Y
antigen is known to influence prenatal sexual differentiation. We look
forward to research that identifies similar subtypes and influences among
lesbians. Blanchard's research provides one example of new interest among
sex researchers in the role of the immune system in sexuality (e.g.,
Binstock, 2001).
DIFFERENCES BETWEEN GAY MEN AND LESBIANS
Several lines of evidence lead to the conclusion that lesbians differ

from gay men on a variety of indicators, suggesting the possibility that
THE GENETICS OF SEXUAL ORIENTATION J5

genetic influence on sexual orientation is different for men and women.
Lesbian women are generally thought to be more bisexual in their behavior
and attractions than gay men, who are more likely to be exclusively homosex-
ual. For example, Bailey and colleagues' (Bailey et al., 2000) study of a
sample of nonheterosexual women and men examined the distribution of
respondents on the Kinsey scale, on which 0 indicates completely heterosex-
ual feelings and 6 indicates compktely homosexual feelings, with the mid-
point, 3, indicating equally heterosexual and homosexual Because the sample
was nonheterosexual, all respondents had scores in the range from 1 to 6.
Women were considerably more likely than men to have a Kinsey score
of 1, whereas men were considerably more likely than women to have a
Kinsey score of 6. Given that the behavioral and psychological patterns are
different for women and men, different explanatory models may be required
for the two groups.
Consistent with this observation, some theories—such as Blanchard's
theory about birth order and the H-Y antigen predisposing men to homo-
sexuality—address male homosexuality only. For the most part, female ho-
mosexuality remains undertheorized.
We should also note, however, that some twin studies show remarkably
consistent concordance rates for lesbians compared with gay men—for exam-
ple, 52% concordance for male MZ twins and 48% concordance for female
twins in a pair of studies from the Bailey group (Bailey & Pillard, 1991;
Bailey et al., 1993). These findings suggest that homosexual orientation is
equally heritable in men and women.
RESEARCH WITH ANIMAL MODELS
Because genetic research on sexual orientation is so difficult with

humans, typically is constrained by small sample sizes, and does not permit
true experimental designs, some researchers are pursuing animal models for
understanding sexual orientation. For example, among domestic sheep 9%
of adult males strongly prefer other males as sex partners (Ellis, 1996; Price,
Katz, Wallach, & Zenchak, 1988). This line of inquiry immediately raises
the question of how one defines sexual orientation in nonhumans. Generally
it is defined as animals' attraction to and sexual contact with members of
their own sex when members of the other sex are available. The definition,
then, is behavioral. We doubt that sheep reflect on their sexual identity.
In Drosophila (fruit flies), a number of genes have been identified that
control distinct aspects of sexual behavior (Emmons & Lipton, 2003). These
include the period gene, which controls one aspect of courtship behavior
(singing), and the courtless gene, which controls one aspect of sex drive. A
mutation of the fruitless (fru) gene leads male fruitflies to have difficulty

discriminating between males and females and to mate with both—although
this hardly seems comparable to bisexual orientation in humans. One re-
search group has identified mutations of several different genes that result
in male-male courtship behavior (Yamamoto & Nakano, 1999).
Zebra finches are a monogamous species that pair-bonds for life. If
female finches are exposed to estradiol or fadrozole (an estrogen synthesis
inhibitor)—and therefore the developing ova are exposed to these hor-
mones—the genetic female offspring pair with another female in adulthood,
even when males are available (Adkins-Regan, 2002). Another experiment
by the same group investigated the importance of early rearing environment.
Young zebra finches normally grow up in the presence of both a mother
and a father, because of the monogamous bond and because both parents
participate in the rearing of offspring. If adult males are removed from the
cages of their chicks, some of the female offspring in adulthood prefer to
bond with another female (Adkins-Regan, 2002). These elegant experiments
provide evidence of both biological influence (hormone exposure during
early development) and the influence of early rearing environment.
ETHICAL ISSUES
Assume for the moment that in the next 10 years, five distinct genes
are identified in humans that are linked to homosexuality, and that if a
baby is born carrying any one of these genes, the baby has a 75% chance
of being homosexual in adulthood. Assume further that prenatal genetic
testing could correctly identify these individuals during the first 3 months
of fetal development. At that point, several scenarios are possible. With
currently available technology, parents could abort such fetuses if they chose
to. This practice currently occurs in many nations around the world in
regard to sex selection. Another possibility is that new technology might
allow gene substitution so that the gay genes could be replaced by heterosex-
ual genes. When reproduction occurs through assisted reproductive tech-
nologies, preimplantation genetic diagnosis would be possible, so that an
embryo could be screened for sexual orientation genes and not implanted
(discarded) if it were carrying one of the homosexual genes (Dahl, 2003).
All of this is within the realm of possibility in the near future and requires
serious ethical consideration.
It is beyond the scope of this chapter to explore all of the ethical
nuances associated with these issues and the legal strategies that might be
necessary depending on the ethical conclusions (for detailed discussions,
see Dahl, 2003; Gabard, 1999; Stein, 1998). The arguments, in brief, are
as follows. Many parents might feel that homosexuals are the victims of
such serious discrimination that the most benevolent approach would be

to choose only heterosexual offspring. Others might respond that such an
approach advocates abortion for essentially frivolous reasons—that most
gays and lesbians lead fulfilling lives and that their condition is not in need
of correcting. The dilemma for parents and for society at large would be
extraordinary.
CONCLUSIONS
Twin studies with humans provide evidence that homosexual orienta-

tion is heritable. At the same time, these studies indicate that sexual orien-
tation is not completely under genetic control, because MZ concordance
rates are substantially below 100%. There is some evidence of a single gene
on the X chromosome affecting sexual orientation in a subset of homosexual
men, although attempts to replicate the findings have produced inconsistent
results. Animal models of sexual orientation are being investigated in diverse
species, including Drosophila, sheep, and finches.
I predict that future research will identify subtypes of gay men and
lesbians with different causal pathways to the distinct subtypes or phenotypes;
these pathways will include single-gene effects, polygenic influences, and
prenatal developmental factors. It is imperative that we as a society consider
the ethical issues that will be involved when these biological influences
are well identified and parents have the possibility of choosing the sexual
orientation of their children.
REFERENCES
Adkins-Regan, E. (2002). Development of sexual partner preference in the zebra

finch: A socially monogamous, pair-bonding animal. Archives of Sexual Behavior,
31, 27-33.
Bailey, J. M., & Bell, A. P. (1993). Familiality of female and male homosexuality.
Behavior Genetics, 23, 313-322.
Bailey, J. M., &. Benishay, D. S. (1993). Familial aggregation of female sexual
orientation. American Journal of Psychiatry, 150, 272-277.
Bailey, J. M., Dunne, M. P., & Martin, N. G. (2000). Genetic and environmental
influences on sexual orientation and its correlates in an Australian twin sample.
Journal of Personality and Social Psychology, 2000, 524-536.
Bailey, J. M., & Pillard, R. C. (1991). A genetic study of male sexual orientation.
Archives of General Psychiatry, 48, 1089-1096.
Bailey, J. M., & Pillard, R. C. (1995). Genetics of human sexual orientation. Annual
Review of Sex Research, 6, 126-150.

Bailey, J. M., Pillard, R. C., Dawood, K., Miller, M. B. Farrer, L. A., Trivedi, S., &
Murphy, R. L. (1999). A family history study of male sexual orientation using
three independent samples. Behavior Genetics, 29, 79-86.
Bailey, J. M., Pillard, R. C, Neale, M. C., & Agyei, Y. (1993). Heritable factors
influence sexual orientation in women. Archives of General Psychiatry, 50, 217-
223.
Bell, A. P., &. Weinberg, M.S. (1978). Homosexualities. New York: Simon &
Schuster.
Binstock, T. (2001). An immune hypothesis of sexual orientation. Medical Hypothe-
ses, 57, 583-590.
Blanchard, R., & Bogaert, A. F. (1996). Homosexuality in men and number of
older brothers. American Journal of Psychiatry, 153, 27-31.
Blanchard, R., & Klassen, P. (1997). H-Y antigen and homosexuality in men.
Journal of Theoretical Biology, 185, 373-378.
Dahl, E. (2003). Ethical issues in new uses of preimplantation genetic diagnosis:
Should parents be allowed to use preimplantation genetic diagnosis to choose
the sexual orientation of their children? Human Reproductions, 18, 1368-1369.
Ellis, L. (1996). The role of perinatal factors in determining sexual orientation. In
R. C. Savin'Williams &. K. M. Cohen (Eds.), The lives of lesbians, gays, and
bisexuals (pp. 35-70). Fort Worth, TX: Harcourt Brace.
Emmons, S. W., & Lipton, J. (2003). Genetic basis of male sexual behavior. Journal
ofNeurobiobgy, 54, 93-110.
Gabard, D. L. (1999). Homosexuality and the human genome project: Private and
public choices. Journal of Homosexuality, 37, 25-51.
Hamer, D., Hu, S., Magnuson, V., Hu, N., & Pattatucci, A. M. (1993, July 16).
A linkage between DNA markers on the X chromosome and male sexual
orientation. Science, 261, 321-327.
Hershberger, S. L. (1997). A twin registry study of male and female sexual orienta-
tion. Journal of Sex Research, 34, 212-222.
Heston, L., & Shields, J. (1968). Homosexuality in twins: A family study and a
registry study. Archives of General Psychiatry, 18, 149-160.
Hu, S., Pattatucci, A., Patterson, C., Li, L., Fulker, D., Cherny, S., et al. (1995).
Linkage between sexual orientation and chromosome Xq28 in males but not
females. Nature Genetics, 11, 248-256.
Hyde, J. S., & DeLamater, J. D. (2003). Understanding human sexuality (8th ed.).
New York: McGraw-Hill.
Kallmann, F. J. (1952a). Comparative twin study on the genetic aspects of male
homosexuality. Journal of Nervous and Mental Disease, 115, 283-298.
Kallmann, F. J. (1952b). Twin and sibship study of overt male homosexuality.
American Journal of Human Genetics, 4, 136-146.
Kendler, K. S., Thornton, L. M., Oilman, S. E., & Kessler, R. C. (2000). Sexual
orientation in a U.S. national sample of twin and nontwin sibling pairs.
American Journal of Psychiatry, 157, 1843-1846.

King, M. N., & McDonald, E. (1992). Homosexuals who are twins: A study of 46
probands. British Journal of Psychiatry, 160, 407-409.
Kinsey, A. C., Pomeroy, W. B., & Martin, C. E. (1948). Sexual behavior in the human
male. Philadelphia: Saunders.
Kinsey, A. C., Pomeroy, W. B., Martin, C. E., & Gebhard, P. H. (1953). Sexual
behavior in the human female. Philadelphia: Saunders.
Laumann, E. O., Gagnon, J. H., Michael, R. T., & Michaels, S. (1994). The social
organization of sexuality: Sexual practices in the United States. Chicago: University
of Chicago Press.
Lever, J., Kanouse, D. E., & Rogers, W. H. (1992). Behavior patterns and sexual
identity of bisexual males, journal of Sex Research, 29, 141-167.
Marshall, E. (1999, October 15). An array of uses: Expression patterns in strawber-
ries, Ebola, TB, and mouse cells. Science, 286, 445.
Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian,
S., et al. (1994, October 7). A strong candidate for the breast and ovarian
cancer susceptibility gene BRCA1. Science, 226, 66-71.
Mustanski, B. S., Chivers, M. L., & Bailey, J. M. (2002). A critical review of recent
biological research on human sexual orientation. Annual Review of Sex Research,
13, 89-140.
Mustanski, B. S., DuPree, M. G., Nievergelt, C. M., Bocklandt, S., Schork, N. J.,
& Hamer, D. (2005, March). A genomewide scan of male sexual orientation.
Human Genetics.
Pillard, R. C., & Bailey, J. N, (1998). Human sexual orientation has a heritable
component. Human Biology, 70, 347-365.
Price, E. O., Katz, L. S., Wallach, S. J. R., & Zenchak, J. J. (1988). The relationship
of male-male mounting to the sexual preferences of young rams. Applied Animal
Behaviour Science, 21, 347-355.
Rice, G., Anderson, C., Risch, N., &. Ebers, G. (1999, April 23). Male homosexual-
ity: Absence of linkage to microsatellite markers at Xq28. Science, 284, 665-
667.
Stein, E. (1998). Choosing the sexual orientation of children. Bioethics, 12, 1-24.
Whitam, F. L., Diamond, M., &. Martin, J. (1993). Homosexual orientation in
twins: A report on 61 pairs and three triplet sets. Archives of Sexual Behavior,
22, 187-206.
Yamamoto, D., & Nakano, Y. (1999). Sexual behavior mutants revisited: Molecular
and cellular basis of Drosophila mating. Cellular and Molecular Life Sciences,
56, 634-646.

THE ROLE OF HYPOTHALAMUS AND
ENDOCRINE SYSTEM IN SEXUALITY
DICK F. SWAAB
Recent research reveals that the hypothalamus and its endocrine sys-
tems exert strong control over sexual behavior and sexual differences. In
this chapter, I explore the nature and workings of this control mechanism.
First, I discuss the mechanisms of sexual differentiation of the brain in
humans and animals, and then I explore the particular way that the hypothal-
amus is differentiated and how different hormone levels affect this process.
Finally, I discuss the control of these systems over sexual behavior and their
possible effect on gender and sexual orientation.
Sexual difference in brain structures necessarily begins to develop early
in any organism. In this section, I explain the various mechanisms of sexual
differentiation. A glossary is included at the end of this chapter.
MECHANISM OF SEXUAL DIFFERENTIATION OF THE BRAIN:

THE AROMATIZATION THEORY
Testosterone is formed in the fetal Leydig cells in the testicle from

about 8 weeks of gestation onward (Hiort, 2000). Sexual differentiation of
I am grateful to W. T. P. Verweij for her excellent secretarial and linguistic help, to J. Kruisbrink for
bibliographic assistance, and to G. van der Meulen and H. Stoffels for the illustrations.
21
the brain is thought to be imprinted or organized by hormonal signals from
the developing male gonads. On the basis of animal experiments, this process
is presumed to be induced by androgens during development, following this
local conversion in the brain to estrogens by P-450 aromatase. In analogy,
male sexual differentiation of the human brain is thus most probably deter-
mined in the two first periods during which peaks in testosterone levels are
found in boys and not in girls, namely (a) during gestation and (b) during
the perinatal period. Subsequently, (c) from puberty onward, sex hormones
alter the function of previously organized neuronal systems ("activating
effects") in both sexes (for references, see De Zegher, Devlieger, & Veldhuis,
1992; Forest, 1989; Swaab, Gooren, & Hofman, 1992; Tucker Halpern,
Udry, & Suchindran, 1998). In late gestation, the male fetus is exposed to
both high concentrations of testosterone from itself and high levels of
estrogens from the placenta. After the inhibitory effect of maternal estrogens
wanes, postnatally, the infant gonadotropins increase, resulting in a rapid
rise of testosterone until some 6 months after birth. The female fetus is
exposed only to estrogens from the placenta. In postnatal female infants
the surge of follicle-stimulating hormone predominates, giving rise to an
increase in estradiol 2 to 4 months postnatally (Quigley, 2002). The possible
importance of the male testosterone surge for sexual differentiation of the
brain following aromatization to estrogens agrees with the observation that
girls whose mothers were exposed to diethylstilboestrol (DES) during preg-
nancy have an increased chance of occurrence of bi- or homosexuality
(Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995; see Table 3.1). Estrogens
produced locally by aromatase are thought to participate in numerous biologi-
cal functions, including sexual differentiation of the brain. Aromatase is
found throughout the adult human brain, with the highest levels in the
pons, thalamus, hypothalamus, and hippocampus. The amount of aromatase
mRNA is highest in the hypothalamus, thalamus, and amygdala. No differ-
ences were detected between the 4 men and 2 women studied (Sasano,
Takahasi, Satoh, Nagura, & Harada, 1998). Such a study has, however, so
far not been performed in larger series and also in development. The neonatal
peak of testosterone is probably not induced by the hypothalamus of the
child but rather by chorionic gonadotrophins from the placenta, because
a normal neonatal increase of testosterone was found in a patient with
hypogonadism based on a DAX-1 gene mutation that causes hypogonadotro-
phic hypogonadism (Takahashi et al., 1997).
Although both sexes are exposed to high placental estrogen levels
prenatally, only males are subjected to high levels of androgens (Quigley,
2002). In human neonates, at 34 to 41 weeks of gestation the testosterone
level is 10-fold higher in men than in women (De Zegher et al., 1992).
Although the peak in serum testosterone in boys at 1-3 months postnatally
approaches the levels seen in adult men, most testosterone is bound to
22 DICK F. SWAAB
TABLE 3.1
Factors That Influence Sexual Differentiation of the Human Brain
Gender Identity (transsexualism)
Chromosomal disorders Rare: 47 XYY (male-to-female), 47 XXX (female-to-male;
Hengstschlager et al., 2003; Turan et al., 2000).
Microdeletion on Y-chromosome in 1 male-to-female
transsexual.
Steroidogenic factor-1 mutations (give XY sex-reversal, no
transsexuality; Achermann, Meeks, & Jameson, 2001;
Achermann, Weiss, Lee, & Jameson, 2001; Correa et al.,
2004; Ozisik, Achermann, & Jameson, 2002).
Klinefelter XXY male-to-female (Sadeghi & Fakhrai, 2000).
Twin studies (Coolidge et al., 2002; Sadeghi & Fakhrai,
2000).
Genomic imprinting (Green & Keverne, 2000).
Phenobarbital/diphantoin (Dessens et al., 1999)
Hormones Intersex (Reiner, 1996; Zucker et al., 1987), micropenis
(Reiner, 2002).
Cloacal exstrophy (Reiner & Gearhart, 2004; Zderic et al.,
2002; Zucker, 2002).
5 oc-reductase deficiency, 17p-hydroxy-steroid-
dehydrogenase-3 deficiency (Imperato-McGinley et al.,
1979, 1991; Wilson, 1999).
Girls with congenital adrenal hyperplasia (CAM) with gender
problems (Meyer-Bahlburg et al., 1996; Slijper et al., 1998;
Zucker et al., 1996).
More polycystic ovaries, oligomenorrhea, and amenorhea
are found in transsexuals (Futterweit et al., 1986).
Complete androgen insensitivity syndrome results in XY
heterosexual females (Wisniewski et al., 2000).
Social factors? (Bradley et al., 1998) not effective: John/Joan/John case
(Cohen-Kettenis & Gooren, 1998; Diamond & Sigmundson,
1997).
Sexual Orientation (homosexuality, heterosexuality)

Genetic factors Twin studies (Bailey & Bell, 1993; Kallman, 1952).
Molecular genetics (Hamer et al., 1993; Hu et al., 1995);
however, see Rice et al. (1999).
Hormones Girls with CAH (Dittmann et al., 1992; Money et al., 1984;
Zucker et al., 1996).
DES (Ehrhardt et al., 1985; Meyer-Bahlburg et al., 1995).
Male-to-female sex reassignment (Bailey et al., 1999).
Chemicals Nicotine prenatally increases the occurrence of lesbianism
(Ellis & Cole-Harding, 2001).
Social factors? Stress during pregnancy (Bailey et al., 1991; Ellis et al.,
1988; Ellis & Cole-Harding, 2001).
Raising by transsexual or homosexual parents does not
affect sexual orientation (Golombok et al., 1983; Green,
1978).
THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 23

globulin. Yet the amount of free testosterone in male infants is about one
order of magnitude larger than that in female infants at this time (Bolton,
Tapanainen, Koivisto, & Vihko, 1989). During the adrenarche (i.e., from
7 years of age to the onset of puberty), the adrenal starts to produce more
androgens, predominantly DHEA (dehydroepiandrosterone) and DHEAS
(dehydroepiandrosterone sulphate). After the age of 8, testosterone from the
adrenal also starts to rise, while a small but significant testicular production of
testosterone is also present in prepubertal boys (Forest, 1989). Although
the testosterone peak during puberty (Forest, 1989) is generally thought to
be involved in activation rather than organization, the neuron number of
the female domestic pig hypothalamus showed a surprising twofold increase
in a sexually dimorphic hypothalamic nucleus around puberty (Van Eerden-
burg & Swaab, 1991), which means that, although this phenomenon may
have been programmed earlier, late organizational effects can at present not
be excluded. Few data are available on the exact period in development
when the human brain differentiates according to sex. Brain weight is
sexually dimorphic from 2 years postnatally onward, taking differences in
body weight between boys and girls into account (Swaab & Hofrnan, 1984).
As I discuss later, sexual differentiation of the human sexually dimorphic
nucleus of the preoptic area (SDN-POA) becomes apparent between 4 years
and puberty (Swaab & Hofman, 1988), and a similar late sexual differentia'
tion was found in the darkly staining posteromedial component of the bed
nucleus of the stria terminalis (BST; Allen, Hines, Shryne, & Gorski, 1989a).
In the central nucleus of the BST (BSTc), the sex difference did not become
significant until early adulthood (Chung, De Vries, & Swaab, 2002). One
might conclude that the limited evidence that is currently available suggests
that sexual differentiation of the human hypothalamus becomes apparent
between 2 years of age and young adulthood, although this may, of course,
be based on processes that were programmed much earlier, for instance by
a peak in sex hormone levels in mid-pregnancy or during the neonatal
period (see before). On the basis of existing prenatal serum samples from
the mother, it appeared that, indeed, higher androgen exposure in the
second trimester of fetal life may masculinize a girl's behavior (Udry, Morris,
& Kovenock, 1995).
Direct Effect of Testosterone
Although the process by.,which estrogens are derived from testosterone

by aromatization is considered feo be the major mechanism for androgeniza-
tion of the brain during development in rodents, testosterone itself may be
of major importance for sexual differentiation of the human brain. In the
first place, both sexes are exposed to high levels of estrogens during fetal
24 DICK F. SWAAB
life, whereas only males are subjected to high androgen levels (Quigley,
2002). Moreover, the androgen receptor, from which the gene that is located
on the X-chromosome at Xqll-12, may be mutated in such a way that the
subject has a complete androgen insensitivity syndrome. Despite normal
testis differentiation and androgen biosynthesis, the phenotype has a normal
female external and behavioral appearance (Batch et al., 1992). Phenotypic
women with complete androgen insensitivity syndrome perceive themselves
as highly feminine. They do not have gender problems and largely report
their sexual attraction, fantasies, and experiences as heterosexual women
(Wilson, 1999; Wisniewski et al., 2000). This means that for the develop-
ment of human male gender identity and male heterosexuality, direct andro-
gen action on the brain seems to be of crucial importance, and that the
aromatization theory may even be of secondary importance for human sexual
differentiation of the brain. The observation by Macke et al. (1993) that
DN A sequence variation in the androgen receptor is not a common determi-
nant of sexual orientation seems to be at variance with these data, but it
should be noted that the DNA variations in that study did not prevent
normal androgenization of the subjects studied, so there was no loss of
function of this receptor. Experiments in rodents and nonhuman primates
now also indicate the importance of androgens for the masculinization of
the brain, not only by regulating transcription of aromatase mRNA (Roselli,
Abdelgadir, &. Resko, 1997; Roselli & Resko, 2001) but also by a direct
effect on the androgen receptor (Sato et al., 2004; Roselli & Resko, 2001).
This point of view agrees with the lack of gender problems in a brother and
a sister with aromatase deficiency due to a mutation (Morishima, Grumbach,
Simpson, Fisher, & Qin, 1995). Moreover, a 28-year-old man with estrogen
resistance due to a mutation of the estrogen-receptor gene was described as
tall, with continued linear growth in adulthood, incomplete epiphysal clo-
sure, and increased estrogen and gonadotrophin levels. A change in a single
base pair in the second exon of the estrogen-receptor gene was found.
However, the patient did not report a history of gender-identity disorder,
had a strong heterosexual interest, and had normal male genitalia. The
elevated serum estrogen levels are explained by a possible compensatory
increase in aromatase activity in response to estrogen resistance (Smith et
al., 1994). The observations in complete androgen sensitivity syndrome
(Wisniewski et al., 2000) and the male gender heterosexual behavior of
patients with 5 OC-reductase-2 or 17pVhydroxy-steroid dehydrogenase-3 defi-
ciency (Imperato-McGinley, Peterson, Gautier, & Sturla, 1979; Imperato-
McGinley et al., 1991; Wilson, 1999; Wilson, Griffin, & Russell, 1993)
indicate that a direct action of testosterone may be more important than
one of dihydrotestosterone or testosterone aromatized to estrogens for male
heterosexual psychosexual development.

Neurotransmitters and Genes
Not only may sex hormones affect sexual differentiation of the brain,
on the basis of animal experiments it is expected that all compounds that
influence hormone or neurotransmitter metabolism in development may
also affect sexual differentiation of the brain (Pilgrim & Reisert, 1992). For
example, young adult male mice that were prenatally exposed to alcohol
were found to have a decreased preference for female partners and an
increased preference for males (Watabe & Endo, 1994). Exposure during
development to some drugs (e.g., barbiturates) causes deviations in testoster-
one levels, persisting into adulthood (Ward, 1992). This agrees with the
finding of Dessens et al. (1999) that children born of mothers who were
exposed to anticonvulsants such as phenobarbital and diphantoin have an
increased probability of transsexuality (see below). Exposure of rats to drugs
such as opiates led to behavioral changes despite apparently normal adult
gonadal hormone levels (Ward, 1992). Similar observations in human sexual
differentiation have not yet been reported. It is of great interest that, in
addition, there is animal experimental evidence for primary genetic control
of sexual differentiation that does not involve sex hormones. Results
obtained from cultures of embryonic rat brain indicate that dopaminergic
neurons may develop morphological and functional sex differences in the
absence of sex steroids (Pilgrim & Reisert, 1992). Candidates for such
hormone'independent effects are those genes located on the nonrecombin'
ing part of the Y-chromosome and believed to be involved in primary sex
determination of the organism. Two candidate genes are the two testis-
determining factors ZFY and the master switch for differentiation of a testis
SRY. Those are putative transcription factors. It has been shown that SRY
and ZFY are transcribed in the hypothalamus and frontal and temporal
cortex of adult men and not in women. It may well be possible that they
function as sex-specific cell-intrinsic signals that are needed for full differenti-
ation of a male human brain, and that continuous expression throughout life
may be required to maintain sex-specific structural or functional properties of
differentiated male neurons. Sexual differentiation of the human brain may
thus be a multifactorial process, although a role of SRY and ZFY in this
process still needs to be proved (Mayer, Lahr, Swaab, Pilgrim, & Reisert,
1998). An alternative mechanism could be the actions of an imprinted
X-linked locus (Skuse, 1999). Microarray studies in mice have shown that
there are over 50 genes expressed in a sexually dimorphic way in the brain
before gonadal differentiation takes place (Dewing, Shi, Horvath, & Vilain,
2003). The relative contributions of the different sex hormones and other
nonhormonal factors on sexual differentiation of the human brain should
clearly be a focus for future research.
26 DICK F. SWAAB
Sexual Differentiation, the Hypothalamus, and the Amygdala
Sex differences in the hypothalamus and other limbic structures are

thought to be the basis of sex differences in sexual arousal (Karama et al.,
2002), reproduction (e.g., copulatory behavior in both sexes, the menstrual
cycle in women), gender identity (i.e., the feeling one is either a man or
a woman), gender identity disorders (transsexuality), and sexual orientation
(homosexuality, heterosexuality, bisexuality; Gooren, Fliers, & Courtney,
1990; Swaab et al., 1992; Swaab & Hofman, 1995). In addition, disinhibited
sexual activity and paraphilias have been reported following lesions in the
hypothalamus and septum (Frohman, Frohman, & Moreault, 2002; Miller,
Cummings, Mclntyre, Ebers, & Grode, 1986). The paraventricular nucleus
(PVN) in rat, and in particular its oxytocin neurons, are involved in erectile
functions in copula. Also, in monkey, penile erection is induced by electrical
stimulation of the PVN (MacLean & Ploog, 1962). Not only oxygen but
also oc-MSH induces erection in rats after intracerebroventricular injection
(Mizusawa, Hedlund, & Andersson, 2002). In humans, the melanocortin
receptor agonist MTII was proerectile in men with organic and psychogenic
erectile dysfunction (MacNeil et al., 2002; Van der Ploeg et al., 2002).
PT-141, another melanocortin agonist, also appeared to be erectogenic in
normal men and in patients with erectile dysfunction. In rodents it appeared
to act by way of the PVN (Molinoff, Shadiack, Earle, Diamond, & Quon,
2003). For penile erections initiated by psychogenic stimuli, the medial
amygdala, the PVN, and to a lesser extent the BST are involved, whereas
medial preoptic lesions in the rat have little, if any, effect on this type of
erection (Liu, Salamone, & Sachs, 1997). Sexual arousal and orgasm produce
long-lasting alterations in plasma prolactin concentrations, both in men
and women (Exton et al., 1999), which might be related to postorgasmic
loss of arousability (Bancroft, 1999), indicating a role of the medial-basal
hypothalamic dopamine neurons.
There is extensive animal experimental literature that shows that the
medial preoptic area (mPOA) of the hypothalamus is a key structure for
male and female copulatory behavior (McKenna, 1998; Pilgrim & Reisert,
1992; Yahr, Finn, Hoffman, & Sayag, 1994) and that the hypothalamus is
involved in seminal vesicle contractions at coitus (Cross & Glover, 1958).
Electrical stimulation of the preoptic area in monkey induces penile erection
(MacLean & Ploog, 1962). However, the exact role of its subarea, the
SDN-POA, in these functions is not clear, and literature on hypothalamic
structures involved in sexual orientation in experimental animals is scarce
(Kindon, Baum, & Paredes, 1996; Paredes, Tzschentke, & Nakach, 1998).
Paredes and Baum (1995) found that lesions of the mPOA/anterior hypothal-
amus in the male ferret not only affected masculine coital performance but

also affected heterosexual partner preference. Perkins and colleagues showed
that testosterone, estron, and estradiol plasma concentrations were higher
in female-oriented rams than in homosexual rams. In the preoptic area, the
aromatase activity was higher in the female-oriented than in the male-
oriented rams, indicating again the possible importance of the preoptic area
in sexual orientation (Resko et al., 1996). Edwards, Walter, and Liang
(1996) observed a decrease in partner preference in male rats following a
lesion of the BST. The content of estrogen receptors in the amygdala was
found to be similar in both homosexual rams and ewes but less than the
receptor content in heterosexual rams, whereas the estrogen receptor content
of the hypothalamus, anterior pituitary, and preoptic area of these two groups
did not differ. These data, and the observations in Kliiver-Bucy syndrome
(see below), suggest that the amygdala might also play a role in sexual
orientation. In sheep, an ovine sexually dimorphic nucleus was identified
in the preoptic area of the hypothalamus that was two times larger in female-
oriented rams than in male-oriented ones. The aromatase mRNA levels in
this nucleus were greater in female-oriented rams than in ewes, whereas the
male-oriented rams had intermediate levels (Roselli, Larkin, Resko, Stellflug,
& Stormshak, 2004).
There is no information available on the exact nature of the preoptic
and amygdala neuronal systems and connections that may be involved in
sexual orientation. Data on the hypothalamus in relation to gender identity
in animals are, of course, nonexistent.
Observations in Humans
A few studies have been presented in the medical literature that

implicate the hypothalamus and adjoining structures in various aspects of
sexual behavior of human and nonhuman primates. In some Kliiver-Bucy
syndrome cases, because of damage of the temporal lobe, patients were
reported to change from heterosexual to homosexual behaviors, indicating
that the temporal lobe might be of importance for sexual orientation (Lilly,
Cummings, Benson, & Frankel, 1983; Marlowe, Mancall, &. Thomas, 1975;
Terzian & Dalle Ore, 1955). Also, there are a few case histories of changing
sexual orientation, from heterosexual to pedophilic or homosexual, on the
basis of a lesion in the hypothalamus or in the temporal lobe, from which
the amygdala has strong connections to the hypothalamus (Miller et al.,
1986). Direct electrical or chemical stimulation of the septum may induce
a sexually motivated state of varying degrees up to penile erection in men
and building up to an orgasm in both sexes (Heath, 1964). Markedly in-
creased sexual behavior was observed following the placement of the tip of
a ventriculoperitoneal shunt into the septum in two cases (Gorman &
Cummings, 1992). Meyers (1961) described a loss of potency following
28 DICK F. SWAAB
lesion in the septo-fornico-hypothalamic region. Electrical stimulation of
the mamillary body in monkeys induced penile erection (MacLean & Ploog,
1962; Poeck & Pilleri, 1965). Precocious puberty and hypersexuality have
been reported following lesions in the posterior part of the hypothalamus,
and hypogonadism is an early sign of pathology in the anterior part of the
hypothalamus (Bauer, 1954, 1959; Poeck & Pilleri, 1965). In particular,
hamartoma that affect the posterior region of the hypothalamus, that is,
those that are pendulated and attached to the region of the mamillary
bodies, may cause precocious puberty (Valdueza et al., 1994). In addition,
precocious puberty is found in cases of pineal region tumors that produce
gonadotropins.
A German stereotactic psychosurgical study (Miiller, Roeder, &.
Orthner, 1973) reported on 22 mainly pedo- or ephebophilic (i.e., preferring
pubertal boys) homosexual men (N = 14) and 6 cases with disturbances of
heterosexual behavior (hypersexuality, exhibitionism, or pedophilia). In 12
homosexual patients, a lesion was made in the right ventromedial nucleus
of the hypothalamus. In 8 patients, homosexual fantasies and impulses
disappeared. According to Miiller et al., in 6 patients a "vivid desire for full
heterosexual contacts" occurred after the operation. In 1 pedophilic patient,
bilateral destruction of the ventromedial nucleus was performed and he lost
all interest in sexual activity after the operation. The heterosexual patients
reported a significant reduction of their sexual drive. Unilateral ventromedial
hypothalamotomy in 14 cases treated for aggressive sexual delinquency
caused a decrease in sexual drive (Albert, Walsh, & Jonk, 1993; Dieckmann,
Schneider-Jonietz, & Schneider, 1988). Although these studies at first sight
appear to suggest that the human ventromedial nucleus of the hypothalamus
is indeed involved in sexual orientation and sexual drive, they are highly
controversial from an ethical point of view and methodologically deficient
(Heimann, 1979; Richer & Sigusch, 1979; Schorsch & Schmidt, 1979).
SEX DIFFERENCES IN THE HYPOTHALAMUS
Sex differences in brain and hormone levels not only are of importance
for sexual behavior but are also thought to be the structural and functional
basis of sex differences in cognition and other central functions, and for the
often pronounced sex differences in the prevalence of neurological and psychi-
atric diseases (Swaab, 2002). There is an increasing amount of data concerning
morphological and functional sex differences, especially in the various nuclei
of the hypothalamus and adjacent structures that are so important for sexual
behavior (see Figures 3.1, 3.2, and 3.3). Functional magnetic resonance
imaging (fMRI) revealed a significant activation of the right-hand-side
hypothalamus in males who were sexually aroused (Arnow et al., 2002).
THE ROLE OF HYPOTHALAML/S AND ENDOCRINE SYSTEM 29

A. B.
LV
AC
SCN
5 mm
Figure 3.1. Topography of the sexually dimorphic structures in the human

hypothalamus. A (left) is a more rostral view than B (right). Abbreviations: Ml = third
ventricle; AC = anterior commissure; BNST-DSPM = darkly staining posteriomedial
component of the bed nucleus of the stria terminals; BSTc = central nucleus of the
bed nucleus of the stria terminalis; FX = fornix; I = infundibulum; INAH1-4 = interstitial
nucleus of the anterior hypothalamus 1-4; LV = lateral ventricle; OC = optic chiasm;
OT=optic tract; PVN = paraventricular nucleus; SCN=suprachiasmatic nucleus; SON =
sexually dimorphic nucleus of the preoptic area; SON = supraoptic nucleus. Scale bar=
5 mm. The AC, BSTc, BNST-DSPM, INAH2,3,4, SCN, and SON vary according to sex.
The SCN, INAH3, and AC are different in relation to sexual orientation.
The hypothalamus contains a number of structurally sexually dimorphic

structures (Figures 3.1, 3.2, and 3.3) that are presumed to be involved in
sexual behavior, such as the SDN-POA, which was first described in the
rat brain by Gorski, Gordon, Shryne, and Southam (1978). Morphometric
analysis revealed that there is also a striking sexual dimorphism in the size
and cell number in the human SDN-POA (Hofman & Swaab, 1989; Swaab
& Fliers, 1985; Swaab & Hofman, 1984; Figures 3.3 and 3.4). In terms of
cell numbers, sexual differentiation of the human SDN-POA occurs after
4 years postnatally (Figure 3.5; see below). This is due to a decrease in both
volume and cell number in women, whereas in men volume and cell number
remain unaltered up to the fifth decade, after which a marked decrease in
cell number is observed as well (Figure 3.4; see below). Sex differences
30 DICK F. SWAAB
Figure 3.2. Thionine (left) and antivasopressin (right) stained section through the
chiasmatic or preoptic region of the hypothalamus. OC = optic chiasm; OVLT =
organum vasculosum lamina terminalis; PVN = paraventricular nucleus; SCN =
suprachiasmatic nucleus; SON = sexually dimorphic nucleus of the preoptic area
(intermediate nucleus, INAH-1); SON = supraoptic nucleus; III = third ventricle. Bar
represents 1 mm.
have also been reported for two other cell groups in the preoptioanterior'
hypothalamus (INAH 2 and 3; Allen, Hines, Shryne, & Gorski, 1989b).
These areas (Figure 3.1) were found to be larger in men than in women,
which was later partly confirmed by LeVay (1991) and Byne et al. (2000).
Other brain regions with a larger volume in men than in women are the
darkly staining posteromedial part of the bed nucleus of the stria terminalis
(BST-dspm), as described by Allen et al. (1989a), and the BSTc (Zhou,
Hofman, Gooren, & Swaab, 1995; Figure 3.6). The sex difference in the
number of vasoactive intestinal polypeptide expressing neurons in the supra-
chiasmatic nucleus (SCN) is age-dependent (Zhou, Hofman, & Swaab,
1995b). The infundibular nucleus shows sex-dependent Alzheimer changes
(Schultz, Braak, & Braak, 1996), and the size of the anterior commissure is

coco
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32 D/CK F. SWAAB
50
Sexually dimorphic nucleus
^ ~
£
-a 30
3
Males
8 20
2
Q
W 10 _
Females
0 20 40 60 80 100
Age (yrs)
Figure 3.4. Age-related changes in the total cell number of the sexually dimorphic
nucleus of the preoptic area (SDN-POA) in the human hypothalamus. The general
trend in the data is enhanced by using smoothed growth curves. Note that in males
SDN-POA cell number steeply declines between the ages of 50 and 70 years, whereas
in females a more gradual cell loss is observed around the age of 70 years. These
curves demonstrate that the reduction in cell number in the human SDN-POA in the
course of aging is a nonlinear, sex-dependent process. From "The Sexually Dimorphic
Nucleus of the Preoptic Area in the Human Brain: A Comparative Morphometric
Study," by M. A. Hofman and D. F. Swaab, 1989, Journal of Anatomy, 164, p. 63.
Copyright 1989 by the Anatomical Society of Great Britain and Ireland. Reprinted
with permission.
sexually dimorphic (Allen & Gorski, 1991). 5-hydroxyindoleacetic acid

levels in the hypothalamus of men were lower than those in women, indicat-
ing a higher turnover rate of 5HT (serotonin) in the female brain (Gottfries,
Roos, & Winblad, 1974). In addition, we found clear age-dependent sex
differences in the activity of the vasopressinergic neurons of the suprooptic
nucleus (SON; Ishunina, Kruijver, Balesar, & Swaab, 2000). A few of these
sex differences are discussed in more detail below.
Sexually Dimorphic Nucleus of the Preoptic Area
There are indications that the area in which the SDN-POA (interstitial
nucleus of the anterior hypothalamus; INAH-1) is situated is involved in
sexual behavior. Electrical stimulation of the median preoptic area in the
rat induces highly exaggerated stimulation-bound sexual behavior (Merari

10=
t_
0)
O
Q.
i
Z
O
10
0.5 | 1 5 10 50 100
Birth Age-postconception (yrs)
Figure 3.5. Developmental and sexual differentiation of the human sexually dimorphic
nucleus of the preoptic area (SDN-POA) of the hypothalamus in 99 subjects, log-log
scale. Note that at the moment of birth the SDN-POA is equally small in boys (A)
and girls (O) and contains about 20% of the cell number found at 2 to 4 years of
age. Cell numbers reach a peak value around 2 to 4 years postnatally, after which
a sexual differentiation occurs in the SDN-POA due to a decrease in cell number in
the SDN-POA of females, whereas the cell number in males remains approximately
unchanged up to the age of 50. The SDN-POA cell number in homosexual men (•)
does not differ from that in the male reference group. The curves are quintic polynomial
functions fitted to the original data for men (full line) and women (dashed line).
From "Sexual Differentiation of the Human Hypothalamus: Ontogeny of the Sexually
Dimorphic Nucleus of the Preoptic Area," by D. F. Swaab and M. A. Hofman, 1988,
Developmental Brain Research, 44, p. 316. Copyright 1988 by Elsevier Science.
Adapted with permission.
& Ginton, 1975). Electrical stimulation of the preoptic area elicited penile
erection in monkeys (MacLean & Ploog, 1962). Although following lesions
of the mPOA, mounting, intromission, and ejaculation are eliminated, the
animals do not lose the ability to achieve an erection (McKenna, 1998).
Although the mPOA does not seem to organize copulatory behavior, it is
crucial for the recognition of sensory stimuli as appropriate sexual targets
and for the integration of this recognition with sexual motivation and
copulatory motor programs. The PVN receives extensive input from the
mPOA of the preoptic area. The oxytocinergic neurons of the PVN project to
34 DICK F. SWAAB
Figure 3.6. Representative sections of the central nucleus of the BST (BSTc)
innervated by vasoactive intestinal polypeptide (VIP): (A) heterosexual man; (B)
heterosexual woman; (C) homosexual man; (D) male-to-female transsexual. Scale
bar = 0.5 mm. BST = bed nucleus of the stria terminalis; LV = lateral ventricle. Note
there are two parts of the BST in A and B: small medial subdivision (BSTm) and large
oval-sized central subdivision (BSTc). A female volume was observed in genetically
male (male-to-female) transsexuals. There was no difference according to sexual
orientation. From "A Sex Difference in the Human Brain and Its Relation to
Transexuality," by J. N. Zhou, M. A. Hofman, L. J. G. Gooren, and D. F. Swaab,
1995, Nature, 378, pp. 68-70. Copyright 1995 by Nature Publishing Group. Reprinted
with permission.
THE ROLE OF HYPOTHALAML7S AND ENDOCRINE SYSTEM 35

the spinal cord and synapse on neurons that innervate the penis (McKenna,
1998). Electrophysiological experiments in rats showed increased multiple
unit activity in the preoptic area during mounting, both in intact males
and females (Kartha & Ramakrishna, 1996). However, the exact role of
the SDN-POA in these functions of the preoptic area is unclear. Although
lesion experiments in rats did indicate that the SDN-POA may be involved
in aspects of male sexual behavior, that is, mounting, intromission, and
ejaculation (De Jonge et al., 1989; Turkenburg, Swaab, Endert, Louwerse,
& Van de Poll, 1988), the effects of lesions on sexual behavior were only
slight, so that it may well be that the major functions of the SDN-POA
are still unknown. Penile erection following mPOA stimulation in monkey
and rat as reported by Giuliano et al. (1996) is considered one of such
putative functions by some authors, but following lesions of the mPOA,
rats do not lose the ability to achieve an erection (McKenna, 1998). Another
possible function as a gakmin-containing sleep-regulating area, homologous
to the ventrolateral preoptic nucleus in the rat (Gaus, Strecker, Tate, Parker,
&. Saper, 2002), is not very probable because of the more medial location
of the SDN-POA in the human. On the basis of a number of animal
experiments, the SDN-POA area is presumed to be involved in sexual
orientation. Lesions of the area of the SDN-POA in the ferret caused a •
significant shift in the males' preference from estrous females to stud males,
that is, from a male-typical pattern of sexual behavior to a more female-
typical pattern (Kindon et al., 1996; Paredes & Baum, 1995). Intact female
rats show a preference for interaction with males, and males show a tendency
to interact with females. After lesion of the mPOA, the females' preference
was not modified. However, mPOA-lesioned male rats changed their partner
preference after the lesion, and the coital behavior of these males was
significantly reduced after the lesion (Paredes et al., 1998). Although in
our studies of the human SDN-POA we did not find differences in size or
cell numbers of this nucleus in relation to sexual orientation (Swaab &
Hofman, 1990), this does, of course, not exclude a functional involvement
of this structure in sexual orientation.
Homology to the Rat SDN-POA
The SDN-POA in the young adult human brain is twice as large in

men (0.20 mm3) as in women (0.10 mm3 on one side) and contains twice
as many cells (Swaab & Fliers, 1985; Figures 3.3 and 3.4). The original
observations on 13 men and 18 women were extended and confirmed in a
group of 103 subjects containing a reference group of 42 men and 38 women
who did not die of a primary neurological or psychiatric disease (Swaab &
Hofman, 1988). Its sexual dimorphism in the human has been confirmed
by H. Braak (see Braak & Braak, 1992, p. 14). The SDN-POA is also present
36 DICK F. SWAAB
in rhesus monkey (Braak & Braak, 1992). The SDN-POA is identical to
the intermediate nucleus described by Brockhaus (1942) and Braak and
Braak (1987) and to the interstitial nucleus of the anterior hypothalamus-1
(INAH-1) of Allen et al. (1989b). Judging by the sex difference in the human
SDN-POA in size and cell number, rostrocaudal position, cytoarchitecture,
peptide, and gamma-ammo butyric acid (GABA) content (see below), this
nucleus is most probably homologous to the SDN-POA in the rat of Gorski
et al. (1978), despite the fact that the rat SDN-POA is located in a more
medial position than its human counterpart (Koutcherov, Mai, Ashwell, &
Paxinos, 2002). The SDN-POA contains galanin (Gai, Geffen, & Blessing
1990), named after its N-terminal residue glycine and its c-terminal alanine
(Tatemoto, Rokaeus, Jornvall, McDonald, & Mutt, 1983), and galanin-
mRNA (Bonnefond, Palacios, Probst, & Mengod, 1990; Gaus et al., 2002).
It should be noted that microinjection of galanin in the medial preoptic
nucleus facilitates female-typical and male-typical sexual behaviors in the
female rat (Bloch, Butler, & Kohlert, 1996). In addition, the SDN-POA
contains th/yrotropin-releasmg hormone (TRH) neurons (Fliers, Noppen,
Wiersinga, Visser, & Swaab, 1994) and glutamic acid decarboxylase (GAD)
65 and 67 (Gao & Moore, 1996a, 1996b). This supports the possible homol-
ogy with the SDN in the rat, in which these peptide- and GABA-containing
neurons have also been described (Bloch, Eckersell, & Mills, 1993; Gao &
Moore, 1996a, 1996b). Moreover, some scattered substance-P neurons are
present in the human SDN-POA (Chawla, Gutierrez, Scott Young, Mc-
Mullen, & Ranee, 1997), and moderate substance-P cell numbers were
found in this area in rat (Simerly, Gorski, & Swanson, 1986).
Although it seems that all the data favor the homology between the
human and the rat SDN-POA and are supported in this by the study of
Koutcherov et al. (2002), it should be noted that others have claimed, on
the basis of the presence of a sex difference, a possible homology between
the rat SDN-POA (Gorski et al., 1978) and the human INAH-3 (Allen
et al., 1989b; Byne et al., 2000; LeVay, 1991). However, this claim did not
take into account a homology in neuropeptide and GABA content of those
nuclei. One of the main arguments against homology between the human
and rat SDN-POA has been the more lateral location of the human nucleus.
In a very detailed developmental study, Koutcherov et al. (2002) have,
however, given an excellent ontogenetic explanation for this seeming dis-
crepancy. By means of immunocytochemistry, my colleagues and I recently
found a more intense staining in men than in women for the androgen
receptor (the receptor for testosterone) and for the estrogen receptors a
and (3 in the SDN-POA, further supporting the presence of a sex difference
in this nucleus (Femandez-Guasti, Kruijver, Fodor, & Swaab, 2000; Kruijver,
Balesar, Espila, Unmehopa, & Swaab, 2002, 2003). Concerning the presence
of estrogen receptors in the SDN-POA, it is relevant to note that an estrogen

response element has been found within the human galanin gene (Howard,
Peng, & Hyde, 1997).
Development and Sexual Differentiation of the SDN-POA
Sexual dimorphism does not seem to be present in the human SDN-

POA at the time of birth. At that moment, total cell numbers are still
similar in boys and girls and the SDN-POA contains no more than some
20% of the total cell number found between 2 to 4 years of age. From birth
up to this age, cell numbers increase equally rapidly in both sexes (Figure
3.5). A sex difference in the SDN-POA does not occur until about the 4th
year postnatally, when cell numbers start to decrease in girls, whereas in
men the cell numbers in the SDN-POA remain stable until their rapid
decrease at approximately 50 years of age, by which time the sex difference
disappears. In women a second phase of marked cell loss sets in after the
age of 70 (Figure 3.4; Hofman & Swaab, 1989; Swaab & Hofman, 1988),
by which time the sex difference emerges again. The sharp decrease in cell
numbers in the SDN-POA later in life may be related to the dramatic
hormonal changes that accompany both male and female senescence (Hof-
man & Swaab, 1989) and to the decrease in male sexual activity around
age 50 (Vermeulen, 1990). However, it is not clear whether the hormonal
changes are directly related to these changes in various functions, either as
cause or as effect of the observed cell loss in this nucleus.
The sex difference in the pattern of aging, and the fact that sexual
differentiation in the human SDN-POA only occurs after the 4th year of
age (Swaab & Hofman, 1988; Figure 3.5), might explain why Allen et al.
(1989b), who had a sample of human adults biased for aged individuals,
did not find a significant sex difference in the size of the SDN-POA, which
they called INAH-1. In Allen et al.'s (1989b) study, 40% of the adult
subjects came from the age group in which the SDN sex difference is
minimal, compared with 29% in our study (Hofman & Swaab, 1989).
Moreover, the age group of elderly subjects (over 70 years of age) was
underrepresented in Allen et al.'s (1989b) study: 20%, compared with the
37.5% that would be a proportional distribution of all ages. In our study,
32% of the subjects belonged to this old age group. So it seems likely that
Allen et al. (1989b) were unable to establish a sex difference in the INAH-1
(SDN-POA) because they used a biased sample. A further argument for
this assumption is that, if we, in our material, had studied only subjects of
the age distribution of Allen et al.'s (1989b) study, the sex difference in
SDN-POA volume would have been reduced from a factor 2 (Hofman &.
Swaab, 1989) to only 1.4 times, and this difference would no longer have
been statistically significant. Moreover, the sex difference in the SDN-POA
emerges only between the ages of 4 and puberty (Swaab & Hofman, 1988);
38 DICK F. SWAAB
therefore the brain of the 5-year-old boy and 4-year-old girl (she indeed
had by far the largest volume of the entire series of female INAH-1) also
produced a bias in the Allen et al. (1989b) study material. The age distribu-
tion, however, does not explain why LeVay (1991) and Byne et al. (2000)
could not confirm the presence of a sex difference in the volume of INAH-1.
Although the numbers of subjects they studied were much smaller than
those in our study (Swaab & Hofman, 1988), technical differences such as
section thickness may be a possible explanation for the controversy. Anyhow,
the finding that nuclear androgen (Figure 3.7) and estrogen receptors a and
P staining in the SDN-POA were more intense in men than in women
(Fernandez-Guasti et al., 2000; Kruijver et al., 2002, 2003) supports the
presence of a functional sex difference in this nucleus.
A prominent theory is that sexual orientation develops as a result of
an interaction between the developing brain and sex hormones (Dorner,
1988; Gladue, Green, & Helleman, 1984). According to Dorner's hypothesis,
homosexual men would have a female differentiation of the hypothalamus.
Although LeVay's (1991) data on the small female-sized IN AH-3 in homo-
sexual men are in agreement with this theory, this idea was not supported
by our data on the SDN-POA in homosexual men. Neither the SDN-POA
volume nor the cell number of homosexual men (Figure 3.6) who had died
of AIDS differed from that of the male reference groups in the same age
range or from that of heterosexuals who also have AIDS (Swaab & Hofman,
1988, 1990). The fact that no difference in SDN-POA cell number was
observed between homosexual and heterosexual men, and the large SCN
found in homosexual men (Swaab & Hofman, 1990), refutes the general
formulation of Dorner's (1988) hypothesis that homosexual men would have
"a female hypothalamus" and rather favors the idea that homosexual men
have a hypothalamus that is different from the hypothalamus of both hetero-
sexual men and heterosexual women. No data are available as yet about
the hypothalamus in lesbian women.
Other Hypothalamic Sexual Dimorphisms
A number of other structural and functional hypothalamic sexual

dimorphisms have been reported.
Structural Differences
In addition to the sex differences observed in the SCN, in the SDN-
POA, and in the BST, Allen et al. (1989b) described two other cell groups
(the interstitial nuclei of the anterior hypothalamus, INAH-2 and -3) that
were larger in the male brain than in the female brain (see Figure 3.1).
Because nothing is known about their neurotransmitter content, it is not
clear at present which nuclei in the rat or rhesus monkey are homologous

Males
Females
Figure 3.7. Schematic representation of the sex differences in the intensity of

androgen receptor immunoreactivity in the human hypothalamus. The denser the
dots, the more intensely stained the receptors for testosterone. Where there are no
dots, no receptors were observed. NBM = nucleus basalis of Meynert; hDBB =
horizontal limb of the diagonal band of Broca; SON = sexually dimorphic nucleus of
the preoptic area; SCN = suprachiasmatic nucleus; BST = bed nucleus of the stria
terminalis; PVN = paraventricular nucleus; SON = supraoptic nucleus; DPe =
periventricular nucleus dorsal zone; VPe = periventricular nucleus ventral zone; fx =
fornix; ox = optic chiasma; 3V = third ventricle; ac = anterior commissure; VMN =
ventromedial hypothalamic nucleus; INF = infundibular nucleus; ot = optic tract; MB =
mamillary body (i.e., MMN [medial mamillary nucleus] + LMN [lateromamillary
nucleus]); cp = cerebral peduncle. From "Sex Differences in the Distribution of
Androgen Receptors in the Human Hypothalamus," by A. Fernandez-Guasti, F. P. M.
Kruijver, M. Fodor, and D. F. Swaab, 2000, Journal of Comparative Neurology, 425,
p. 426. Reprinted with permission.
40 DICK F. SWAAB
to the human INAH-2 and -3. There is a discrepancy in the literature
concerning the sex difference in the size of INAH-2 as described by Allen
et al. (1989b) that could not be confirmed by LeVay (1991) or by Byne et
al. (2000). The fact that LeVay did not observe a smaller INAH-2 in women
was proposed to be explained by an age-related sex difference in this nucleus.
INAH-2 shows this sex difference only after the child-bearing age, with
one exception: a 44-year-old woman who had a hysterectomy with ovarian
removal 3 years prior to her death and who had a small INAH-2 (Allen
et al., 1989b). The sex difference in INAH-2 thus seems to come to expres-
sion only after menopause, when circulating estrogens are absent. This would
also explain why LeVay could not confirm the difference in INAH-2 in his
group of young patients. The sex difference in INAH-2 was considered to
be the first human example of a sex difference depending on circulating
levels of sex hormones, that is, a difference based on a lack of activating
effects of sex hormones in menopause rather than on organizing effects of
sex hormones in development. However, Byne et al. (2000) could not
confirm the relationship between INAH-2 and reproductive status as sug-
gested by the data of Allen et al. (1989b).
4
Sex Hormone Receptor Distribution Differences

In most hypothalamic areas that contain androgen receptor staining,
nuclear staining in particular is less intense in women than in men (Figure
3.7).The strongest sex difference was found in the lateral and the medial
mamillary nucleus (MMN; Fernandez-Guasti et al., 2000). The mamillary
body complex is known to be involved in several aspects of sexual behavior,
such as arousal of sexual interest and penile erection (Fernandez-Guasti et
al., 2000; MacLean &. Ploog, 1962). In addition, a sex difference in androgen
receptor staining was present in the horizontal diagonal band of Broca,
SDN-POA, mPOA, the dorsal and ventral zone of the periventricular nu-
cleus (PVN), SON, ventromedial hypothalamic nucleus, and the infundibular
nucleus. However, no sex differences were observed in androgen receptor
staining in the BST, the nucleus basalis of Meynert, and the island of Calleja
(Fernandez-Guasti et al., 2000). Nuclear androgen receptor activity in the
mamillary complex of heterosexual men did not differ from that of homosex-
ual men, but it was significantly stronger than in women. A femalelike
pattern was found in 26- and 53-year-old castrated men and in intact old
men. These data indicate that the amount of nuclear receptor staining in
the mamillary complex is dependent on the circulating levels of androgens
rather than on gender identity or sexual orientation. This idea is supported
by the finding that a malelike pattern of androgen-receptor staining was
found in a 36-year-old bisexual noncastrated male-to-female transsexual and
a heterosexual virilized woman of 46 years of age (Kruijver, Fernandez-

Guasti, Fodor, Kraan, & Swaab, 2001). Various sex differences were observed
for estrogen receptor a (ERa) staining in the hypothalamus and adjacent
areas of young human subjects. More intense nucleus ERa immunoreactivity
was found in young men compared with young women, for example, in the
SDN-POA, the SON, and the PVN. Women showed a stronger nuclear
ERa-immunoreactivity in the SCN and MMN. No sex differences in nuclear
ERa staining were found in, for example, the BSTc, the islands of Calleja
(Cal), or in the infundibular nucleus (INF).
A more intense nuclear ER|3 staining was found in men, for example,
in neurons of the BSTc, the islands of Calleja, and the SDN-POA. Women
showed more nuclear ERP staining in the SCN, the SON, the PVN, the
INF, and the MMN.
Observations in subjects with abnormal hormone levels showed, in
most areas, ER|3-immunoreactivity distribution patterns according to the
level of circulating estrogens, suggesting that the majority of the reported
sex differences in ERp-immunoreactivity are "activational" rather than "or-
ganizational" in nature (Kruijver et al., 2002, 2003).
Sex Differences in the Supraoptic and Paraventricular Nucleus
Not only does vasopressin act as an antidiuretic hormone, it is also

involved in penile erection (Segarra et al., 1998; see below). Although my
colleagues and I did not find a sex difference in vasopressin neuron number
in the SON or PVN, a sex difference was reported in vasopressin plasma
levels. Men have higher vasopressin levels than women (Asplund & Aberg,
1991; Van Londen et al., 1997). In addition, it was found that the posterior
lobe of the pituitary is larger in boys than in girls (Takano, Utsunomiya,
Ono, Ohfu, & Okazaki, 1999). This sex difference is explained by the higher
activity we found in vasopressin neurons in the SON in young men as
compared with young women as determined by the size of the Golgi appara-
tus. In the course of aging, probably triggered by the decrease in estrogen
levels, the neuronal activity gradually increases in women, but it remains
stable in men. The sex difference in neuronal activity in the SON thus
disappears after the age of 50 (Ishunina, Salehi, Hofman, & Swaab, 1999).
This is an example of a hypothalamic system that does not show a structural
sex difference but rather a functional sex difference. It is also an example
of a sex difference based on the activating (or in this case inhibiting) effect
of sex hormones in adulthood.
The activation of neurosecretory vasopressin neurons in postmeno-
pausal women was confirmed by in situ hybridization (Ishunina, Salehi, &
Swaab, 2000) and by measuring the cell size as a parameter for neuronal
activity. The vasopressin neurons in the SON and PVN appeared to be
larger in young men than in young women. In elderly women (>50 years
42 DICK F. SWAAB
old), vasopressin cell size considerably exceeded that of young women. In
addition, vasopressin cell size correlated positively with age in women but
not in men. Sex differences in the size of the PVN vasopressin neurons
were pronounced at the left side and absent at the right side, indicating
the presence of functional lateralization of this nucleus. No difference was
found in any morphometric parameter of oxytocin neurons in the PVN
among the four groups studied. These data demonstrate sex differences in
the size of the vasopressin neurons, and thus presumably in their function,
that are age- and probably also side-dependent, and the absence of such
changes in oxytocin neurons in the PVN (Ishunina & Swaab, 1999). The
activation of vasopressin neurons in postmenopausal women is probably
mediated by a decrease in the presence of estrogen receptor- (3 in these
neurons and an increase in estrogen receptor a nuclear staining (Ishunina,
Kruijver, Balesar, & Swaab, 2000).
The low-affinity neurotrophin receptor p75 (p75NTR) may be involved
in the mechanism of activation of vasopressin neurons in postmenopausal
women. This receptor was found to be expressed in the SON neurons of
aged individuals, whereas p75NTR expression was shown to be suppressed by
estrogens in a cell line. My colleagues and I investigated whether p75NTR
immunoreactivity in SON neurons was age- and sex-dependent in post-
mortem brains of control patients ranging in age from 29 to 94 years old
with an anti-p75NTRantibody and determined the area of p75NTR immunoreac-
tivity per neuron profile using an image analysis system. To study whether
the p75NTR might also participate in the activation of SON neurons, we
related Golgi apparatus size to the amount of p75NTR in the same patients.
P75NTR immunoreactivity indeed correlated significantly with age and with
Golgi-apparatus size, but only in women, not in men. These observations
suggest that p75NTR modulates the effects of estrogens on vasopressinergic
neurons in the human SON (Ishunina, Salehi, & Swaab, 2000).
Oxytocin and vasopressin are thought to be involved in affiliation,
including pair bonding, parental care, and territorial aggression, in monoga-
mous animals (Insel, 1997; Young, Wang, & Insel, 1998); maternal behavior;
and other aspects of reproductive behavior (Anderson-Hunt &. Dennerstein,
1995; L. S. Carter, 1992; Insel, 1992; McKenna, 1998). Human sexually
dimorphic reactions to pheromones (Savic, Berglund, Gulyas, &. Roland,
2001) may affect such processes in the PVN. Lesions in the male rat PVN
also indicate that this nucleus is involved in erection and that the magno-
cellular and parvicellular elements play different parts in this function (Liu
et al., 1997). Electrical stimulation of the PVN in squirrel monkeys elicited
penile erection (MacLean & Ploog, 1962). Electrical stimulation of the
dorsal penile nerve or of the glans penis excited 60% of the oxytocin cells
in the contralateral and ipsilateral SON of the rat (Honda et al., 1999). In
another experiment, too, oxytocin cells of the PVN were found to be

activated by sensory information from the penis. In the male rat, oxytocin
is an extremely potent inducer of penile erection (Argiolas, Melis, & Gessa,
1986; McKenna, 1998). Because intracerebroventricular injection of an
oxytocin antagonist reduced noncontact penile erections in rat dose-
dependently, the involvement of central oxytocin in the expression of penile
erections does not only seem to be a pharmacological effect but to have a
physiological function as well (Melis, Spano, Succu, & Argiolas, 1999).
The direct contractile effects of vasopressin on penile blood vessels, together
with its amplifying effects on adrenergic-mediated constriction, support the
idea that circulating vasopressin may also be involved in penile erection
(Segarra et al., 1998). Tactile stimulation of the penis during male copulatory
behavior further activates oxytocin cells, both in the PVN and in the SON,
and this seems to induce both central and peripheral oxytocin release.
Excitatory aminoacid transmission increases in the PVN during noncontact
erections. This may contribute to the nitric-oxide production in the PVN
and activates oxytocin neurons, thus mediating this sexual response (Melis,
Succu, Spano, & Argiolas, 2000). Dopamine neurotransmission to the PVN
is also supposed to be involved in penile erection (Chen, 2000). In addition,
oxytocin may reduce maternal aggression in a period shortly after the birth,
when lactating females show naturally high levels of this behavior (Gio-
venardi, Padoin, Cadore, & Lucion, 1998). In women, basal levels of oxyto-
cin during lactation are associated with a desire to please, give, and interact
socially (Uvnas-Moberg, Alster, Petersson, Sohlstrom, & Bjorkstrand, 1998).
Oxytocin released during labor and lactation may influence human maternal
responsiveness and perhaps attachment (C. S. Carter, 1998). The increased
oxytocin levels in cerebrospinal fluid during labor in human are presumed
to be associated with the induction of maternal behavior (Takeda, Kuwabara,
& Mizuno, 1985).
In a number of cases milk "let-down," indicating oxytocin release, has
been reported during the sexual act in women who were in their lactating
period (Campbell & Petersen, 1953). In men, oxytocin may also be involved
in sexual arousal and ejaculation (Carmichael et al., 1987; Murphy, Seckl,
Burton, Checkley, & Lightman, 1987). In women, too, oxytocin secretion
seems to be related to smooth muscle contractions during orgasm (Car-
michael et al., 1987). One minute after orgasm, oxytocin levels are increased
in women (Blaicher et al., 1999). In agreement with this case report, oxytocin
levels are known to rise during sexual arousal and peak during orgasm in
both women and men. In multiorgasmic subjects, oxytocin peaks immedi-
ately prior to and during terminative orgasm, that is, the oxytocin peak
coincides with sexual satiation. The intensity of orgasmic contractions, but
not their duration, correlate positively with increases in oxytocin levels.
Naloxon decreases the level of pleasure at orgasm and blocks the periorgasmic
rise of oxytocin levels (Carmichael, Warburton, Dixen, & Davidson, 1994;
44 DICK F. SWAAB
Murphy, Checkley, Seckl, & Lightman, 1990). Administration of vasopres-
sin inhibits copulatory behavior in female rats, whereas a vasopressin antago-
nist facilitated the lordosis response (Meyerson, Hoglund, Johansson, Blom-
qvist, & Ericson, 1988). Both in men and women, oxytocin induces
contractions of smooth muscle cells and may thus facilitate transport of
eggs and sperm (Carmichael et al., 1994). Animal experiments in rat confirm
the possibility of such roles (Ackerman, Lange, & Clemens, 1998). In female
animals, oxytocin was found to facilitate estrus, sexual arousal, receptivity,
and other mating behaviors, including lordosis. An as yet unconfirmed
case report has described a woman who began to take a contraceptive pill
containing progesterone only. She experienced accentuated physiological
and psychological sexual arousal after she had coincidentally used a pre-
scribed synthetic oxytocin spray for let-down of breast milk (Anderson-
Hunt, 1994; Anderson-Hunt & Dennerstein, 1995).
Animal experiments show a mechanism of interaction between sex
hormones and oxytocin by initiating the production of receptors for this
peptide (Anderson-Hunt & Dennerstein, 1995). Oxytocin is also produced
by the male reproductive tract and modulates not only its contractility but
also steroidogenesis. The finding that the oxytocin receptor is present in
the interstitial tissue and in Sertoli cells in the testes supports the presence
of such biological actions of oxytocin (Frayne & Nicholson, 1998). Indeed,
oxytocin levels are significantly higher in women on oral contraceptives,
and oxytocin levels recorded during the menstrual week are significantly
lower than at other times (Uvnas-Moberg, Sjogren, Westlin, Andersson, &
Stock, 1989). Oxytocin plasma levels increase on estrogen administration
(Kostoglou-Athanassiou, Athanassio, Treacher, Wheeler, & Forsling, 1998).
The plasma concentration of vasopressin during the menstrual o
cycle is
doubled on Days 16 to 18 as compared with Day 1 (Forsling, Akerlund, &
Stromberg, 1981), whereas others found a tendency of vasopressin to increase
on Days 11 to 13, when peak concentrations of estradiol occur (Punnonen
et al., 1983). Not only were the basal vasopressin levels higher in the
follicular phase of the natural menstrual cycle, their nocturnal peaks were
also higher (Kostoglou-Athanassiou, Athanassiou, Treacher, Wheeler, &.
Forsling, 1998). Increased oxytocin plasma levels were reported in a few
women around the time of ovulation (Mitchell, Haynes, Anderson, &
Turnbull, 1980).
TRANSSEXUALITY AND THE BED NUCLEUS OF

THE STRIA TERMINALIS
Transsexuality is a rare condition. The annual incidence of transsexual-

ity in Sweden has been estimated to be 0.17 per 100,000 inhabitants. The

sex ratio (genetic male:female) varies from country to country between 1.4:1
and 3:1 (Garrels et al., 2000; Landen, Walinder, & Lundstrom, 1996). There
is only little information about the factors that may influence gender and
cause transsexuality in humans (see Table 3.1). For gender identity disorder
early in development, a strong (62%) hereditary component was found on
the basis of twin studies (Coolidge, Thede, & Young, 2002). The disparate
maternal aunt-uncle ratio in transsexual men has been hypothesized to be
due to genomic imprinting, that is, a different effect depending on whether
the gene is paternally or maternally inherited (Green & Keveme, 2000).
There are only a few reports that have found chromosomal abnormalities
in transsexuals. Six cases of male-to-female transsexuals with 47,XYY chro-
mosome and one female-to-male transsexual with 47,XXX have been re-
ported (Turan et al., 2000). Moreover, transsexualism has been reported in
a man with Kleinfelter (XXY). In addition, pairs of monozygotic female
twins have requested sex reassignment, and twin studies and familial cases
of gender identity problems suggest a genetic basis for this disorder (Coolidge
et al., 2002; Green, 2000; Sadeghi & Fakhrai, 2000). Although only a
minority of the transsexuals has an underlying endocrine abnormality (Meyer
et al., 1986), there are some indications of a possible disorder of the
hypothalamo'pituitary gonadal axis in some transsexuals that may have
a basis in development, such as a high frequency of polycystic ovaries,
oligomenorrhea, and amenorrhea in female-to-male transsexualism (Fut-
terweit, Weiss, & Fagerstrom, 1986; Sadeghi & Fakhrai, 2000).
Dessens et al. (1999) reported that three children born of a group of
243 women exposed to the anticonvulsants phenobarbital and diphantoin
were found to be transsexuals, while, in addition, there were a few other
subjects with gender dysphoria/cross-gender behavior. Gender problems thus
occurred remarkably often in view of the rarity of this disorder. This exciting
observation on the effect of compounds that are known to alter steroid
levels in animal experiments has to be examined further. In this respect, it
is of interest to note that phenobarbital has been widely used as prophylactic
treatment in neonatal jaundice and greatly elevated the postnatal rise in
testosterone (Forest, Lecog, Salle, & Bertrand, 1981). In 1996, Meyer-
Bahlburg et al. reported a gender change from woman to man in four 46,XX
individuals with classical congenital adrenal hyperplasia (CAH). Congenital
adrenal hyperplasia, characterized by high androgen levels during prenatal
development, indeed constitutes a risk factor for the development of gender
identity problems (Slijper et al., 1998). Although it should be emphasized
that the large majority of women with this disorder do not experience a
marked gender identity conflict, the odds ratio that a genetic female with
this disease would live, as an adult, in the male social role compared with
genetic females in the general population was found to be 608:1 (Zucker
et al., 1996). These observations support the view that intrauterine or
46 DICK F. SWAAB
perinatal exposure to abnormal levels of sex hormones may permanently
affect gender identity.
The concept of sexual neutrality at birth after which infants differenti-
ate as masculine or feminine as a result of social experiences was proposed
by Money, Hampson, and Hampson (1955a, 1955b). Gender imprinting
was presumed to start at the age of 1 year and to be already well established
by 3 to 4 years of age (Money & Erhardt, 1972). Observations on children
with male pseudohermaphroditism due to S-a-reductase-Z deficiency were
supposed to support the influence of life experience on psychosexual makeup
(Al-Attia, 1996). A classic report that has strongly influenced the opinion
that the environment plays a crucial role in gender development was the
one described by Money of a boy whose penis was accidentally ablated at
the age of 8 months during a phemosis repair by cautery and who was
subsequently raised as a girl. Orchiectomy followed within a year to facilitate
feminization. This individual was initially described as developing into a
normally functioning woman. Later, however, it appeared that the individual
had rejected the sex of raising and switched at puberty to living as a man
again, and he requested male hormone shots, a mastectomy, and phalloplasty.
At the age of 25 he married a woman and adopted her children. This famous
John-Joan-John story, although it is just one case, illustrates that there is
little, if any, support for the view that individuals are sexually neutral
at birth and that normal psychosexual development is dependent on the
environment of the genitals (Colapinto, 2001; Diamond & Sigmundson,
1997). This unfortunate story had a very sad ending. "John" committed
suicide in May 2004.
In a second case of penile ablation in which the decision was made
to reassign the patient as a girl and raise the baby as a girl, the remainder
of the penis and testes were removed at a slightly earlier stage, at 7 months.
Although her adult sexual orientation was bisexual and she was mainly
attracted to women, her gender identity was female. The different outcome
as compared with the former case is explained by the authors on the basis
of the earlier decision to reassign the sex (Bradley, Oliver, Chernick, &
Zucker, 1998). A third case, which did not get much attention, was a boy
who lost his penis at the age of 6 months. A sex reassignment to the female
gender was performed. However, in adolescence the patient refused hormone
treatment and requested reassigment to a boy. Phalloplasty was performed
by court order (Ochoa, 1998).
Male patients with cloacal exstrophy have a herniation of the urinary
bladder and hindgut, and the anatomy leaves them aphalic in the majority
of cases, although the testicles are normal from a histological point of
view.
In a group of 8 male patients who were gender reassigned as females
and orchidectomized in the neonatal period, at least in 3 instances gender

identity has been questioned by the patients themselves (Zderic, Canning,
Carr, Kodman-Jones, & Snyder, 2002), supporting the early programming
of gender identity by biological factors and arguing against a dominating
role of the social environment. The observation that in longitudinal series
of 16 hormonally normal 46XY males assigned to female sex-of-rearing at
birth, due to the absence of a penis, 8 have spontaneously declared them-
selves male and 15 fall very close to the male-typical spectrum of gender
roles (Reiner, 2002), leads to the same conclusion. In a follow-up of this
study, 8 of the 14 male subjects who were sex-reassigned as females declared
themselves male. This study also indicates that the prenatal androgens are
the major biological factor for the development of male gender identity,
even in the absence of the neonatal and pubertal androgen surges (Reiner
& Gearhart, 2004).
Reiner (1996) described a 46XY child with mixed gonadal dysgenesis,
one immature testis, hypoplastic uterus, and clitoral hypertrophy, who was
raised without stigmatization as a girl but who declared himself male at the
age of 14- Following corrective surgery and testosterone substitution, he lived
as a boy despite the social factors that were clearly in favor of maintaining the
assigned sex. Apparently the deficient testis had been able to organize the
brain during development even though the hormone levels were prenatally
so inadequate that ambiguity of the genitalia was induced.
A child with true hermaphroditism, 45X (13%) 47XYY (87%) sex
chromosome mosaic pattern in blood, uterus, fallopian tubes, phallus, testicu-
lar tissue, and epididymis, was assigned the male sex at birth. At 5 weeks
the decision was made to reassign him to female. At 9 months an operation
was performed to make the genitalia female, at 13 months the testicle was
removed, and at the age of 5 another operation was done to make the
genitalia female. She was raised as a girl but had masculine interests, and
when she was around 8 years of age she declared that "God had made a
mistake" and that she "should have been a boy." The male sex hormones
to which she had been exposed in utero had apparently imprinted the male
gender, although the authors also presumed postnatal psychosocial factors
to have played a role (Zucker, Bradley, & Hughes, 1987).
We recently found a female-sized BSTc in male-to-female transsexuals.
This supports the hypothesis that gender identity develops as a result of an
interaction between the developing brain and sex hormones. The BST is
situated at the junction of the hypothalamus, septum, and amygdala (Lesur,
Caspar, Alvarez, &. Berger, 1989; Walter, Mai, Lanta, & Gores, 1991; Figure
3.1) and plays an essential part in rodent sexual behavior (Liu et al., 1997).
Estrogen and androgen receptors have been found in the human BST
(Fernandez-Guasti et al., 2000; Kruijver et al., 2002), and it is a major
aromatization center in the developing rat brain (i.e., converting androgens
48 DICK F. SWAAB
into estrogens). The BST in rat receives projections, mainly from the
amygdala, and provides a strong input in the preoptic-hypothalamic region.
Reciprocal connections between the hypothalamus, BST, and amygdala are
well documented in experimental animals (Liu et al, 1997; Zhou, Hofman,
Gooren, & Swaab, 1995). There is a strong innervation of galanin fibers
in the BST, and galanin receptors have also been shown in this structure
(Mufson et al., 1998). The BST and centromedial amygdala have common
cytO' and chemo'architectonic characteristics, and these regions are consid-
ered to be two components of one distinct neuronal complex. Neurons in the
substantia innominata form cellular bridges between the BST and amygdala
(Heimer, 2000; Lesur et al., 1989; Martin, Powers, Dellovade, & Price,
1991; Walter et al., 1991). In most mammals, including humans, the ex-
tended amygdala presents itself as a ring of neurons encircling the internal
capsule and the basal ganglia (Heimer, Harlan, Alheid, Garcia, & De Olmos,
1997). The BST-amygdala continuum contains, for example, leutinizing
hormone-releasing hormone (LHRH) neurons (Ranee et al., 1994). How-
ever, tyrosine-hydroxylase mRNA has been found by others in these struc-
tures (Gouras, Ranee, Scott Young, & Koliatsos, 1992).
Five principal sectors have been identified in the BST, including a darkly
staining posteromedial component (dspm) of the BST (Allen et al., 1989a;
Kruijver et al., 2000; Lesur et al., 1989; Martin et al., 1991). This part of the
BST is situated in the dorsolateral zone of the fornix (Figure 3.1) and is sexually
dimorphic (Figure 3.6). This sex difference does not seem to occur before
adulthood. Its chemical composition and relationship to the other four
principal BST sectors (see above) is unknown. Although the BST contains
nuclear androgen receptors, no sex difference in the staining of this receptor
was observed (Fernandez-Guasti et al., 2000; Figure 3.7).
The volume of the BST-dspm is 2.5 times larger in men than in women
(Allen et al., 1989a). My colleagues and I have found that the BSTc, which
was defined by its dense vasoactive intestinal polypeptide (VIP) innervation
(Figure 3.6) or by its somatostatin fibers and neurons, is sexually dimorphic.
The BSTc is 40% smaller in women than in men and contains also some
40% fewer somatostatin neurons (Figure 3.6). No relationship was observed
between BSTc volume or somatostatin cell number and sexual orientation:
In the heterosexual reference group and a group of homosexual men, a
similar BSTc volume and somatostatin cell number were observed. The size
and somatostatin cell number of the BSTc were, moreover, not influenced
by abnormal hormone levels in adulthood. However, a remarkably small
BSTc (40% of the male reference volume and somatostatin neuron number)
was observed in a group of 6 male-to-female transsexuals (Figures 3.6 and
3.9). These data suggest that the female size of this nucleus in male-to-
female transsexuals was established during development and that the BSTc

is part of a network that might be involved in gender, that is, the feeling
of being either a man or a woman (Kruijver et al., 2000; Zhou, Hofman,
Gooren, &. Swaab, 1995).
HOMOSEXUALITY AND HYPOTHALAMIC STRUCTURES
Sexual orientation is influenced by quite a number of genetic as well

as nongenetic factors (see Table 3.1). Genetic factors appear from studies
in families, in twins, and through molecular genetics (Bailey & Bell, 1993;
Bailey et al., 1999; Hamer, Magnuson, Hu, & Pattatucci, 1993; Hu et al.,
1995; Kallman, 1952; Pillard & Bailey, 1998; Turner, 1995). Hamer and
colleagues found linkage between DNA markers on the X-chromosome and
male sexual orientation. Genetic linkage between the microsatellite markers
on the X chromosome (i.e., Xq28) was detected for the families of gay men
but not for the families of lesbians (Hamer et al., 1993, Hu et al., 1995).
In a follow-up study, Rice, Anderson, Risch, and Ebers (1999) studied the
sharing of alleles at position Xq28 in 52 Canadian gay male sibling pairs.
Allele and haplotype sharing for these markers was not increased more than
expected, which did not support the presence of an X-linked gene underlying
male homosexuality. In a reaction to Rice et al.'s article, Hamer (1999)
stated that (a) the family pedigree data from the Canadian study supported
his hypothesis, (b) three other available Xq28 DNA studies found linkage,
and (c) the heritability of sexual orientation is supported by substantial
evidence independent of the X-chromosome data. In a meta-analysis of the
four available studies, Hamer found a significant linkage. Rice et al. re-
sponded extensively and remained convinced that an X-linked gene could
not exist in the population with any sizable frequency. This controversy
will undoubtedly continue for a while longer. Aromatase cytochrome P450
(CYP19), which is necessary for the conversion of androgen to estrogens,
was studied as a candidate gene for male homosexuality in homosexual
brothers. However, the study revealed no indications that variation in this
gene may be a major factor for the development of male homosexuality
(DuPree, Mustanski, Bocklandt, Nievergelt, & Hamer, 2004).
Sex hormones during development also have an influence on sexual
orientation, as appears from the increased proportion of bisexual and
homosexual girls with CAH (Dittmann, Kappes, &. Kappes, 1992; Meyer-
Bahlberg et al., 1996; Money, Schwartz, & Lewis, 1984; Zucker et al.,
1996). Then there is DES, a compound related to estrogens that increases
the occurrence of bisexuality or homosexuality in girls whose mothers
received DES during pregnancy (Ehrhardt et al., 1985; Meyer-Bahlburg
et al., 1995) to prevent miscarriage (which it does not do). Whether
environmental estrogens from plastics can influence sexual differentia-
50 DICK F. SWAAB
tion of the human brain and behavior is, at present, in debate but
certainly not established. In addition, phytoestrogens, such as resveratrol,
present in grapes and wine and an agonist for the estrogen receptor, should
be considered in this respect (Gehm, McAndrews, Chien, & Jameson,
1997).
Maternal stress is thought to lead to increased occurrence of homosexu-
ality in boys (Ellis, Ames, Peckham, & Burke, 1988) and girls (Bailey,
Willerman, & Parks, 1991), and nicotine prenatally increases the occurrence
of lesbianism (Ellis & Cole-Harding, 2001). As an interesting case history
of this prenatal environmental factor, Weyl (1987) mentioned that Marcel
Proust's mother was subjected to the overwhelming stress of the Paris com-
mune during the 5th month of her pregnancy in 1871 and that Mary, Queen
of Scots, the mother of the homosexual king of England, James I, toward
the end of the 5th month of pregnancy had the terrifying experience that
her secretary and special friend Riccio was killed. Although postnatal social
factors are generally presumed to be involved in the development of sexual
orientation (Byne & Pearson, 1993; Zucker et al., 1996), solid evidence in
support of such an effect has not yet been reported. The observation that
children raised by lesbian couples or by transsexuals generally have a hetero-
sexual orientation (Golombok, Spencer, & Rutter, 1983; Green, 1978; Kirk-
patrick, Smith, & Roy, 1981) does not support the possibility of the social
environment in which the child is raised as an important factor for determin-
ing sexual orientation, nor is there scientific support for the idea that homo-
sexuality has psychoanalytical or other psychological or social learning expla-
nations, or that it would be a "lifestyle choice" (Ellis, 1996).
Various hypothalamic structures are structurally different in relation
to sexual orientation, that is, the SCN, INAH-3, and the commissura
anterior, suggesting that a difference in hypothalamic neuronal networks
that occurs in development may be the basis of differences in sexual orienta-
tion. In addition to its possible involvement in reproduction (see below),
the SCN might also play a role in sexual orientation. In fact, the first
difference in the human brain in relation to sexual orientation was observed
in the SCN. Morphometric analysis of the SCN of 10 homosexual men
revealed that the volume of this nucleus was 1.7 times larger than that of
a reference group of 18 presumed heterosexual men, and that it contained
2.1 times as many cells (Figure 3.8; Swaab & Hofman, 1990). In fact, the
same high number of SCN vasopressin neurons as observed in 1- to 2-year-
old children (Swaab, Hofman, & Honnebier, 1990) were also found in
homosexual men. It seems as if the programmed postnatal cell death, which
seems to begin in the SCN between 13 to 16 months after birth, does not
occur to the same extent in homosexual men. The increased number of
vasopressin-expressing neurons in the SCN of homosexual men appeared
to be quite specific for this subgroup of neurons, because the number of
THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 5]

SUPRACHIASMATIC NUCLEUS SEXUALLY DIMORPHIC NUCLEUS
0.6 r ** ***
0.5
0.4
<D 0.3
o 0.2
0.1
Homo Hetero Homo Hetero
125 *** **
W
0 100
T—
X
75
££
3
= 50
CD
U
15
25
Homo Hetero Homo Hetero
20
** ***
o
15
.a5
E
3
C
=CD 10
O
C
'55
w
a> 5
a.
8
(C
Reference Homo- Hetero-

group sexuals sexuals
(AIDS) (AIDS)
Figure 3.8. Top: Volume of the human suprachiasmatic nucleus (SCN) and sexually
dimorphic nucleus of the preoptic area (SON) as measured in three groups of adult
subjects: a male reference group (Ref; n = 18); male homosexuals who died of AIDS
(Homo; n = 1 0); heterosexuals who died of AIDS (Hetero; n = 6; 4 men and 2 women).
(caption continued on next page)
52 DICK F. SWAAB
VlP-expressing neurons was not changed. However, in both the vasopressin
and VIP neurons in the SCN, a reduced nuclear diameter was observed in
homosexual men, suggesting metabolic alterations in the SCN in relation
to sexual orientation (Zhou, Hofman, & Swaab, 1995a).
There are indeed a number of experimental data and observations on
human material that indicate that the SCN is involved in aspects of sexual
behavior and reproduction. Already in the early 1970s, postcoital ultrastruc-
tural changes indicating neuronal activation were reported in the SCN of
the female rabbit (Clattenburg, Singh, & Montemurro, 1972). Important
is also that the activity of SCN neurons increases suddenly around puberty
(Anderson, 1981), indicating the addition of a reproductive function to the
already mature circadian functions of the SCN. In addition, efferents of the
SCN innervate the preoptic area that is involved in reproductive behaviors.
Extensive lesioning of the SCN area results in failure of ovulation in the
female rat (Brown-Grant & Raisman, 1977). The ovarian reproductive
cycle is controlled by the SCN, probably through a direct monosynaptic
innervation of LHRH neurons by VIP fibers (Van der Beek, Horvath,
Wiegant, Van den Hurk, & Buijs, 1997; Van der Beek, Wiegant, Van der
Donk, Van den Hurk, & Buijs, 1993). Several morphological sex differences
have been reported that support putative reproductive functions. The SCN
of male rats contains a larger amount of axo-spinal synapses, postsynaptic
density material, and asymmetrical synapses, and their neurons contain more
nucleoli than those of female rats (Giildner, 1982, 1983). The sex difference
in synaptic number in the rat SCN depends on androgens in development
(Le Blond, Morris, Karakiulakis, Powell, &. Thomas, 1982). In gerbils the
volume of the SCN is sexually dimorphic (Holman & Hutchison, 1991)
and so is the organization of astroglia in the SCN (Collado, Beyer, Huchison,
& Holman, 1995).
Figure 3.8. (caption continued from previous page). The values indicate medians
and the standard deviation of the median. The differences in the volume of the
SCN between homosexuals and the subjects from both other groups are statistically
significant (Kruskal-Wallis multiple comparison test, *p < .05; **p < .01; ***p < .001).
Note that none of the parameters measured in the SON (A,B) showed significant
differences among the three groups (p always > 0.4). Middle: Total number of cells
in the human SCN and SON. The SCN in homosexual men contains 2.1 times as
many cells as the SCN in the reference group of male subjects and 2.4 times as many
cells as the SCN in heterosexual AIDS patients. Bottom: The number of vasopressin
neurons in the human SCN (the SON does not contain vasopressin-producing cells).
The SCN in homosexual men contains, on average, 1.9 times as many vasopressin
neurons as the SCN in heterosexual AIDS patients. Notice that the SCN of
heterosexual individuals who died of AIDS contains fewer vasopressin cells than the
SCN of the subjects from the reference group. From "An Enlarged Suprachiasmatic
Nucleus in Homosexual Men," by D. F. Swaab and M. A. Hofman, 1990, Brain
Research, 537, p. 144. Copyright 1990 by Elsevier. Reprinted with permission.

A sex difference was found in the shape of the vasopressin subdivision
of the human SCN (Swaab, Fliers, & Partiman, 1985), and a sex difference
was observed in the number of VIP-containing neurons in the human SCN.
The number of VIP-expressing neurons in the SCN is larger in men of 10
to 40 years and larger in women of 41 to 65 years of age (Swaab, Zhou,
Ehlhart, & Hofman, 1994; Zhou, Hofman, & Swaab, 1995b). These observa-
tions are also consistent with sexually dimorphic functions of the SCN that
must, however, still be better defined. It is interesting to note, moreover, that
the pineal hormone 5-methoxytryptophol shows significant sex differences:
Plasma concentrations increase in boys and decrease in girls after the age
of 8 (Moiin-Carballo et al, 1996).
In seasonal breeders, VIP immunoreactivity in the SCN changes in
relation to seasonal fluctuations in sexual activity (Lakhdar-Ghazal,
Kalsbeek, &. Pevet, 1992). The activation of c-fos in the SCN by sexual
stimulation also points to a role of the SCN in reproduction (Pfaus, Kleo-
poulos, Mobbs, Gibbs, & Pfaff, 1993). Bakker, Van Ophemert, and Slob
(1993) have found that male rats treated neonatally with the aromatase
inhibitor 1,4,6androstratriene-3,l 7-dione (ATD) showed a clear sexual part-
ner preference for females when tested in the late dark phase. When tested
in the early dark phase, however, they showed a lesser preference for the
female, or no preference at all. This is the first indication of the involvement
of the clock (i.e., the SCN) in sexual orientation. The number of vasopressin-
expressing neurons in the SCN of these ATD-treated bisexual animals was
increased (Swaab et al., 1995), something that was also found in homosexual
men (Swaab & Hofman, 1990). This observation supports the possibility
that the increased number of vasopressin-expressing neurons in the SCN
of adult homosexual men reflects a difference in the early stages of develop-
ment in the brain.
Moreover, LeVay (1991) found that INAH-3 was twice as large in
heterosexual men as in homosexual men. INAH-2 in the human hypothala-
mus is said to correspond to the anterocentral nucleus in the rhesus monkey
and INAH-3 to the dorsocentral portion of the anterior hypothalamic
nucleus in the rhesus monkey (Byne, 1998). Allen and Gorski (1992)
found that the anterior commissure was larger in homosexual men than in
heterosexual men.
CONCLUSIONS
Sex differences in the brain and in hormone levels are thought to be

the structural and functional basis of pronounced sex differences of all aspects
of sexual behavior. On the basis of animal experiments, sexual differentiation
of the brain is thought to be imprinted or organized by androgens during
54 DICK F. SWAAB
CO
o 70
AS5
O 60
CO
CO
50 A FMT
0
.Q
E 40 A 82
13
C T4 •
S3
2 30
=3
0)
c
20
T2 •
cd
*-> PO
CO T3 •
o 10 S1
03
E
o
CO
M HM TM
Figure 3.9. Central nucleus of the bed nucleus of the stria terminalis (BSTc) neuron
numbers. Distribution of the BSTc neuron numbers among the different groups
according to sex, sexual orientation, and gender identity: M (heterosexual male
reference group), HM (homosexual male group), F (female group), TM (male-to-
female transsexuals). The sex hormone disorder patients S1,2,3,5,6, and M2 indicate
that changes in sex hormone levels in adulthood do not change the neuron numbers
of the BSTc. The difference between the M and the TM group (<.04) becomes also
statistically significant according to the sequential Bonferonni method if S2, S3, and
S5 are included in the M group or if S7 is included in the TM group (p < .01). Note
that the number of neurons of the female-to-male transsexual (FMT) is fully in the
male range. A = AIDS patient. The BSTc number of neurons in the heterosexual man
and woman with AIDS remained well within the corresponding reference group (see
also Figure 3.1), so AIDS did not seem to affect the somatostatin neuron numbers
in the BSTc. P = Postmenopausal woman; S1 (& 25 years of age) = Turner syndrome
(45,XO; ovarian hypoplasia); M2 (& 73 years of age) = postmenopausal status. From
"Male-to-Female Transsexuals Have Female Neuron Numbers in a Limbic Nucleus,"
by F. P. M. Kruijver, J. N. Zhou, C. W. Pool, M. A. Hofman, L. J. G. Gooren, and
D. F. Swaab, 2000, Journal of Clinical Endocrinology and Metabolism, 85, p. 2036.
Copyright 2000 by The Endocrine Society. Reprinted with permission.
development, following conversion by aromatase to estrogens, presumably

during gestation or the perinatal period. From puberty onward, sex hormones
alter the function of previously organized neuronal systems. This action is
known as activating effects of sex hormones, but such effects may also inhibit
neuronal function. However, genetic males with a complete androgen insen-
sitivity syndrome, despite their normal testis differentiation and androgen

biosynthesis, have a phenotype that is normal female, both external and in
their behavior. They perceive themselves as highly feminine and do not
have gender problems. This means that for the development of human male
gender identity and male heterosexuality, direct androgen action on the
brain seems to be of crucial importance. The aromatization theory may thus
be of secondary importance for human sexual differentiation.
Apart from the interactions of hormones and the developing neurons,
a number of factors seem to influence sexual differentiation of the brain
and thus sexual orientation and gender identity. Chromosomal disorders,
genetic factors, stress during pregnancy, and medicines taken by the pregnant
mother may play a role. Postnatal social factors do not seem to be of primary
importance for the development of sexual orientation or gender identity.
Focusing on the hypothalamus and adjacent areas, sex differences have
been reported in volume and cell numbers, in neuronal metabolic activity
of brain areas, and in their transmitter content that seem to be related to
reproduction, gender identity, and sexual orientation. The BSTc, a brain
area involved in reproduction, was found to be twice as large in men as in
women. In male-to-female transsexuals, this sex difference was found to be
reversed (Figure 3.9). The BSTc of the genetically male transsexuals was
found to be of female size and neuron number, supported by the idea that
this structure may be involved in the feeling to be a man or a woman.
The BSTc in transsexuals thus seems to have followed a course of sexual
differentiation during development that is opposite to that of the sex organs.
The interaction among hormones, hypothalamic structures, and the
amygdala seem to be of the utmost importance for sexual behavior. Disorders
of sexual behavior may not only go together with decreased hormone levels
in elderly people but also be due to countless neurological, neuroendocrine,
or psychiatric diseases and therefore demand careful diagnostic attention.
REFERENCES
Achermann, J. C., Meeks, J. J., &. Jameson, J. L. (2001). Phenotypic spectrum of

mutations in DAX-1 and SF-1. Molecular and Cellular Endocrinology, 185,
17-25.
Achermann, J. C., Weiss, J., Lee, E.-J., & Jameson, J. L. (2001). Inherited disorders
of the gonadotropin hormones. Molecular and Cellular Endocrinology, 179,
89-96.
Ackerman, A. E., Lange, G. M., & Clemens, L. G. (1998). Effects of paraventricular
lesions on sex behavior and seminal emission in male rats. Physiology and
Behavior, 63, 49-53.
Al-Attia, H. M. (1996). Gender identity and role in a pedigree of Arabs with
intersex due to 5 alpha reductase-2 deficiency. Psychoneuroendocrinology, 21,
651-657.
56 DICK F. SWAAB
Albert, D. J., Walsh, M. L, & Jonk, R. H. (1993). Aggression in humans: What is
its biological foundation? Neuroscience and Biobehavioral Reviews, 17, 405-425.
Allen, L. S., &. Gorski, R. A. (1991). Sexual dimorphism of the anterior commissure
and massa intermedia of the human brain. Journal of Comparative Neurology,
312, 97-104.
Allen, L. S., & Gorski, R. A. (1992). Sexual orientation and the size of the anterior
commissure in the human brain. Proceedings of the National Academy of Sciences
USA, 89, 7199-7202.
Allen, L. S., Hines, M., Shryne, J. E., & Gorski, R. A. (1989a). Sex difference in the
bed nucleus of the stria terminalis of the human brain. Journal of Comparative
Neurobgy, 302, 697-706.
Allen, L.S., Hines, M., Shryne, J. E., &. Gorski, R. A. (1989b). Two sexually
dimorphic cell groups in the human brain. Journal of Neuroscience, 9, 497-506.
Anderson, C. H. (1981). Nucleolus: Changes at puberty in neurons of the suprachi-
asmatic nucleus and the preoptic area. Experimental Neurology, 74, 780-786.
Anderson-Hunt, M. (1994). Increased female sexual response after oxytocin. British
Medical Journal, 309, 929.
Anderson-Hunt, M., & Dennerstein, L. (1995). Oxytocin and female sexuality.
Gynecologic and Obstetric Investigation, 40, 217-221.
Argiolas, A., Melis, M. R., & Gessa, G. L. (1986). Oxytocin: An extremely potent
inducer of penile erection and yawning in male rats. European Journal of
Pharmacology, 130, 265-272.
Arnow, B. A., Desmond, J. E., Banner, L. L., Glover, G. H., Solomon, A., Lake
Polan, M., et al. (2002). Brain activation and sexual arousal in healthy, hetero-
sexual males. Brain, 125, 1014-1023.
Q
Asplund, R., & Aberg, H. (1991). Diurnal variation in the levels of antidiuretic
hormone in the elderly. Journal of Internal Medicine, 229, 131-134.
Bailey, J. M., & Bell, A. P. (1993). Familiality of female and male homosexuality.
Behavior Genetics, 23, 313-322.
Bailey, J. M., Pillard, R. C., Dawood, K., Miller, M. B., Farrer, L. A., Trivedi, S.,
&. Murphy, R. L. (1999). A family history study of male sexual orientation
using three independent samples. Behavior Genetics, 29, 79-86.
Bailey, J. M., Willerman, L., & Parks, C. (1991). A test of the maternal stress
theory of human male homosexuality. Archives of Sexual Behavior, 20, 277-293.
Bakker, J., Van Ophemert, J., & Slob, A. K. (1993). Organization of partner prefer-
ence and sexual behavior and its nocturnal rhythmicity in male rats. Behavioral
Neuroscience, 107, 1-10.
Bancroft, J. (1999). Cardiovascular and endocrine changes during sexual arousal
and orgasm. Psychosomatic Medicine, 61, 290-291.
Batch, J. A., Williams, D. M., Davies, H. R., Brown, B. D., Evans, B. A. J, Hughes,
I. A., & Patterson, M. N. (1992). Role of the androgen receptor in male sexual
differentiation. Hormone Research, 38, 226-229.

Bauer, H. G. (1954). Endocrine and other clinical manifestations of hypothalamic
disease: A survey of 60 cases, with autopsies. Journal of Clinical Endocrinology,
14, 13-31.
Bauer, H. G. (1959). Endocrine and metabolic conditions related to pathology in
the hypothalamus: A review. Journal of Nervous Mental Disease, 128, 323-338.
Blaicher, W., Gruber, D., Bieglmayer, C., Blaicher, A. M., Knogler, W., & Huber,
J. C. (1999). The role of oxytocin in relation to female sexual arousal. Gyneco'
logic and Obstetric Investigation, 47, 125-126.
Bloch, G. J., Butler, P. C., &. Kohlert, J. G. (1996). Galanin microinjected into the
medial preoptic nucleus faciliates female- and male-typical sexual behaviors
in the female rat. Physiology and Behavior, 59, 1147-1154.
Bloch, G. J., Eckersell, C., & Mills, R. (1993). Distribution of galanin-immunoreac-
tive cells within sexually dimorphic components of the medial preoptic area
of the male and female rat. Brain Research, 620, 259-268.
Bolton, N. J., Tapanainen, J., Koivisto, M., & Vihko, R. (1989). Circulating sex
hormone-binding globulin and testosterone in newborns and infants. Clinical
Endocrinology, 31, 201-207.
Bonnefond, C., Palacios, J. M., Probst, A., & Mengod, G. (1990). Distribution of
galantn mRNA containing cells and galanin receptor binding sites in human
and rat hypothalamus. European Journal ofNeuroscience, 2, 629-637.
Braak, H., & Braak, E. (1987). The hypothalamus of the human adult: Chiasmatic
region. Anatomy and Embryology, 176, 315-330.
Braak, H., & Braak, E. (1992). Anatomy of the human hypothalamus (chiasmatic
and tuberal region). In D. F. Swaab, M. A. Hofman, M. Mirmiran, R. Ravid,
& F. W. Van Leeuwen (Eds.), Progress in brain research: Vol. 93. The human
hypothalamus in health and disease (pp. 3-16). Amsterdam: Elsevier.
Bradley, S. J., Oliver, G. D., Chernick, A. B., & Zucker, K. J. (1998). Experiment
of nurture: Ablatio penis at 2 months, sex reassignment at 7 months and a
psychosexual follow-up in young adulthood. Pediatrics, 102, 1-5.
Brockhaus, H. (1942). Beitrag zur normalen Anatomic des Hypothalamus und der
Zona incerta beim Menschen. [Contribution to the normal anatomy of the
human hypothalamus and zona inserta.] Journal of Psychological Neurology,
51, 96-196.
Brown-Grant, K., &. Raisman, G. (1977). Abnormalities in reproductive function
associated with the destruction of the suprachiasmatic nuclei in female rats.
Proceedings of the Royal Society of London Series B, 198, 279-296.
Byne, W. (1998). The medial preoptic and anterior hypothalamic regions of the
rhesus monkey: Cytoarchitectonic comparison with the human and evidence
for sexual dimorphism. Brain Research, 793, 346-350.
Byne, W., Lasco, M. S., Kemether, E., Shinwari, A., Edgar, M. A., Morgello, S.,
et al. (2000). The interstitial nuclei of the human anterior hypothalamus: An
investigation of sexual variation in volume and cell size, number and density.
Brain Research, 856, 254-258.
58 DICK F. SWAAB
Byne, W., & Pearson, B. (1993). Human sexual orientation: The biological theories
reappraised. Archives of General Psychiatry, 50, 228-239.
Campbell, B., & Petersen, W. E. (1953). Milk "let-down" and the orgasm in the
human female. Human Biology, 25, 165-168.
Carmichael, M. S., Humbert, R., Dixen, J., Palmisano, G., Greenleaf, W., & David-
son, J. M. (1987). Plasma oxytocin increases in the human sexual response.
Journal of Clinical Endocrinology and Metabolism, 64, 27-31.
Carmichael, M. S., Warburton, V. L, Dixen, J., & Davidson, J. M. (1994). Relation-
ships among cardiovascular, muscular, and oxytocin responses during human
sexual activity. Arc/lives of Sexual Behavior, 23, 59-79.
Carter, C. S. (1998). Neuroendocrine perspectives on social attachment and love.
Ps;yc/ioneuroeruiocrino{ogy, 23, 779-818.
Carter, L. S. (1992). Oxytocin and sexual behavior. Neuroscience and Biobehavioral
Review, 16, 131-144.
Chawla, M. K., Gutierrez, G. M., Scott Young, W., Ill, McMullen, N. T., & Ranee,
N. E. (1997). Localization of neurons expressing substance P and neurokinin
B gene transcripts in the human hypothalamus and basal forebrain. Journal of
Comparative Neurology, 384, 429-442.
Chen, K.-K. (2000). Paraventricular nucleus of hypothalamus: A brain locus in
central neural regulation of penile erection in the rat. International Journal of
Andrology, 23(Suppl. 2), 81.
Chung, W. C. J., De Vries, G. J., & Swaab, D. F. (2002). Sexual differentiation of
the bed nucleus of the stria terminalis in humans may extend into adulthood.
Journal of Neuroscience, 22, 1027-1033.
Clattenburg, R. E., Singh, R. P., & Montemurro, D. G. (1972). Postcoital ultrastruc-
tural changes in neurons of the suprachiasmatic nucleus of the rabbit. Zeitschrift
fur Zellforschung, 125, 448-459.
Cohen-Kettenis, P. T., & Gooren, L. J. G. (1998). Transsexual ism: A review of
etiology, diagnosis and treatment. Journal of Psychosomatic Research, 46, 315-
333.
Colapinto, J. (2001). As nature made him: The boy who was raised as a girl. New
York: Perennial.
Collado, P., Beyer, C., Hutchison, J. B., & Holman, S. D. (1995). Hypothalamic
distribution of astrocytes is gender-related in Mongolian gerbils. Neuroscience
Letters, 184, 86-89.
Coolidge, F. L., Thede, L. L., & Young, S. E. (2002). The heritability of gender
identity disorder in a child and adolescent twin sample. Behavior Genetics,
32, 251-257.
Correa, R. V., Domenice, S., Bingham, N. C., Billerbeck, A. E. C., Rainey, W. E.,
Parker, K. L., & Mendonca, B. B. (2004). A microdeletion in the ligand binding
domain of human steroidogenic factor 1 causes XY sex reversal without adrenal
insufficiency. Journal of Clinical Endocrinology and Metabolism, 89, 1767-1772.

Cross, B. A., & Glover, T. D. (1958). The hypothalamus and seminal emission.
Journal of Endocrinology, 16, 385-395.
De Jonge, F. H., Louwerse, A. L., Ooms, M. P., Evers, P., Endert, E., & Van de
Poll, N. E. (1989). Lesions of the SDN-POA inhibit sexual behaviour of male
Wistar rats. Brain Research Bulletin, 23, 483-492.
De Zegher, F., Devlieger, H., & Veldhuis, J. D. (1992). Pulsatile and sexually
dimorphic secretion of luteinizing hormone in the human infant on the day
of birth. Pediatric Research, 32L, 605-607.
Dessens, A. B., Cohen-Kettenis, P. T., Mellenbergh, G. J., Van de Poll, N. E.,
Koppe, J. G., &. Boer, K. (1999). Prenatal exposure to anticonvulsants and
psychosexual development. Archives of Sexual Behavior, 28, 31-44-
Dewing, P., Shi, T., Horvath, S., &. Vilain, E. (2003). Sexually dimorphic gene
expression in mouse brain precedes gonadal differentiation. Molecular Brain
Research, 118, 82-90.
Diamond, M., & Sigmundson, K. (1997). Sex reassignment at birth: Long-term
review and clinical implications. Archives of Pediatric Adolescent Medicine,
151, 298-304.
Dieckmann, G., Schneider-Jonietz, B., & Schneider, H. (1988). Psychiatric and
neuropsychological findings after stereotactic hypothalamotomy, in cases of
extreme sexual aggressivity. Acta Neurochirurgica, 44(Suppl.), 163-166.
Dittmann, R. W., Kappes, M. E., & Kappes, M. H. (1992). Sexual behavior in
adolescent and adult females with congenital adrenal hyperplasia. Ps^c/ionewro-
endocrinology, ]/, 153-170.
Dorner, G. (1988). Neuroendocrine response to estrogen and brain differentiation
in heterosexuals, homosexuals, and transsexuals. Archives of Sexual Behavior,
17, 57-75.
DuPree, M. G., Mustanski, B. S., Bocklandt, S., Nievergelt, C., &. Hamer, D. H.
(2004). A candidate gene study of CYPig (Aromatase) and male sexual orienta-
tion. Behavior Genetics, 34, 243-250.
Edwards, D. A., Walter, B., &. Liang, P. (1996). Hypothalamic and olfactory control
of sexual behavior and partner preference in male rats. Physiology and Behavior,
60, 1347-1354.
Ehrhardt, A. A., Meyer-Bahlburg, H. F. L., Rosen, L. R., Feldman, J. F., Veridiano,
N. P., Zimmerman, I., & McEwen, B. S. (1985). Sexual orientation after prena-
tal exposure to exogenous estrogen. Archives of Sexual Behavior, 14, 57-75.
Ellis, L. (1996). Theories of homosexuality. In R. C. Savin-Williams & K. M.
Cohen (Eds.), The lives of lesbians, gays, and bisexuals: Children to adults
(pp. 11-70). Ft. Worth, TX: Harcourt Brace College.
Ellis, L., Ames, M. A., Peckham, W., & Burke, D. (1988). Sexual orientation of
human offspring may be altered by severe maternal stress during pregnancy.
Journal of Sex Research, 25, 152-157.
Ellis, L., &. Cole-Harding, S. (2001). The effects of prenatal stress, and of prenatal
alcohol and nicotine exposure, on human sexual orientation. Physiology and
Behavior, 74, 213-226.
60 DICK F. SWAAB
Exton, M. S., Bindert, A., Kriiger T., Scheller, F., Hartmann, U., & Schedlowski, M.
(1999). Cardiovascular and endocrine alterations after masturbation-induced
orgasm in women. Psychosomatic Medicine, 61, 280-289.
Fernandez-Guasti, A., Kruijver, F. P. M., Fodor, M., & Swaab, D. F. (2000). Sex
differences in the distribution of androgen receptors in the human hypothala-
mus. Journal of Comparative Neurology, 425, 422-435.
Fliers, E., Noppen, N. W. A. M., Wiersinga, W. M., Visser, T. J., & Swaab, D. F.
(1994). Distribution of thyrotropin-releasing hormone (TRH)-containing cells
and fibers in the human hypothalamus. Journal of Comparative Neurology,
350, 311-323.
Forest, M. G. (1989). Physiological changes in circulating androgens. Pediatric and
Adolescent Endocrinology, 19, 104-129.
Forest, M. G., Lecoq, A., Salle, B., & Bertrand, J. (1981). Does neonatal phenobarbi-
tal treatment affect testicular and adrenal functions and steroid binding in
plasma in infancy? Journal of Clinical Endocrinology and Metabolism, 52, 103-
110.
o
Forsling, M. L., Akerlund, M., &. Stromberg, P. (1981). Variations in plasma concen-
trations of vasopressin during the menstrual cycle. Journal of Endocrinolgy,
89, 263-266.
Frayne, J., & Nicholson, H. D. (1998) Localization of oxytocin receptors in the
human and macaque monkey male reproductive tracts: Evidence for a physio-
logical role of oxytocin in the male. Molecular Human Reproduction, 4, 527-532.
Frohman, E. M., Frohman, T. C., & Moreault, A. M. (2002). Acquired sexual
paraphilia in patients with multiple sclerosis. Archives of Neurology, 59, 1006-
1010.
Futterweit, W., Weiss, R. A., & Fagerstrom, R. M. (1986). Endocrine evaluation
of forty female-to-male transsexuals: Increased frequency of polycystic ovarian
disease in female transsexualism. Arc/lives of Sexual Behavior, 15, 69-77.
Gai, W. P., Geffen, L. B., & Blessing, W. W. (1990). Galanin immunoreactive
neurons in the human hypothalamus: Colocalization with vasopressin-contain-
ing neurons. Journal of Comparative Neurology, 298, 265-280.
Gao, B., & Moore, R. Y. (1996a). Glutamic acid decarboxylase message isoforms
in human suprachiasmatic nucleus. Journal of Biological Rhythms, 11, 172-179.
Gao, B., &. Moore, R. Y. (1996b). The sexually dimorphic nucleus of the hypothala-
mus contains GABA neurons in rat and man. Brain Research, 742, 163-171.
Garrels, L., Kockott, G., Michael, N., Preuss, W., Renter, K., Schmidt, G., et al.
(2000). Sex ratio of transsexuals in Germany: The development over three
decades. Acta Psychiatrica Scandinavica, 102, 445-448.
Gaus, S. E., Strecker, R. E., Tate, B. A., Parker, R. A., & Saper, C. B. (2002).
Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in
multiple mammalian species. Neuroscience, 115, 285-294-
Gehm, B. D., McAndrews, J. M., Chien, P. Y., & Jameson, J. L. (1997). Resveratrol,
a polyphenolic compound found in grapes and wine, is an agonist for the
THE ROLE OF HYPOTHALAMl/S AND ENDOCRINE SYSTEM 61

estrogen receptor. Proceedings of the National Academy of Sciences USA, 94,
14138-14143.
Giovenardi, M., Padoin, M. J., Cadore, L. P., &Lucion, A. B. (1998). Hypothalamic
paraventricular nucleus modulates maternal aggression in rats: Effects of ibo-
tenic acid lesion and oxytocin antisense. Physiology and Behavior, 63, 351-359.
Giuliano, F., Rampin, O., Brown, K., Courtois, F., Benoit, G., & Jardin, A. (1996).
Stimulation of the medial preoptic area of the hypothalamus in the rat elicits
increases in intracavernous pressure. Neuroscience Letters, 209, 1-4.
Gladue, B. A., Green, R., & Helleman, R. E. (1984, September 28). Neuroendocrine
response to estrogen and sexual orientation. Science, 225, 1496-1499.
Golombok, S., Spencer, A., & Rutter, M. (1983). Children in lesbian and single-
parent households: Psychosexual and psychiatric appraisal. Journal of Child
Psychology and Psychiatry, 4, 551-572.
Gooren, L. J. G., Fliers, E., & Courtney, K. (1990). Biological determinants of
sexual orientation. Annual Review of Sex Research, I, 175-196.
Gorman, D. G., & Cummings, J. L. (1992). Hypersexuality following septal injury.
Archives of Neurology, 49, 308-310.
Gorski, R. A., Gordon, J. H., Shryne, J. E., & Southam, A. M. (1978). Evidence
for a morphological sex difference within the medial preoptic area of the rat
brain. Brain Research, 148, 333-346.
Gottfries, C. G., Roos, B. E., & Winblad, B. (1974). Determination of 5-hydroxy-
tryptamine, 5-hydroxyindoleacetic acid and homovanillic acid in brain tissue
from an autopsy material. Acta Ps;ychiatrica Scandinavica, 50, 496-507.
Gouras, O.K., Ranee, N. E., Scott Young, W., Ill, &. Koliatsos, V. E. (1992).
Tyrosine-hydroxylase-containing neurons in the primate basal forebrain mag-
nocellular complex. Brain Research, 584, 287-293.
Green, R. (1978). Sexual identity of 37 children raised by homosexual or transsexual
parents. American Journal of Psychiatry, 135, 692-697.
Green, R. (2000). Family cooccurrence of "gender dysphoria": Ten sibling or parent-
child pairs. Archives of Sexual Behavior, 29, 499-507.
Green, R., & Keverne, E. B. (2000). The disparate maternal aunt-uncle ratio in
male-transsexuals: An explanation invoking genomic imprinting. Journal of
Theoretical Biology, 202, 55-63.
Giildner, F.-H. (1982). Sexual dimorphisms of axo-spine synapses and postsynaptic
density material in the suprachiasmatic nucleus of the rat. Neuroscience Letters,
28, 145-150.
Giildner, F.-H. (1983). Numbers of neurons and astroglial cells in the suprachi-
asmatic nucleus of male and female rats. Experimental Brain Research, 50, 373-
376.
Hamer, D. H. (1999, August 6). Genetics and male sexual orientation. Science,
285, 803a.
62 DICK F. SWAAB
Hamer, D. H., Magnuson, V. L., Hu, N., & Pattatucci, A. M. L. (1993, July 16).
A linkage between DNA markers on the X chromosome and male sexual
orientation. Science, 261, 321-327.
Heath, R. G. (Ed.). (1964). The role of pleasure in behavior. New York: Hoeber
Medical Division, Harper & Row.
Heimann, H. (1-979). Psychiatrische, psychologische, soziologische und ethische
implikationen psychochirurgischer MaBnahmen unter besonderer Beriick-
sichtigung der Hypothalamotomie bei Sexualdeviationen [Psychiatric, psycho-
logical, sociological, and ethical implications of psychosurgery in particular of
hypothalectomy in sexual deviation]. Nervenartz, 50, 682-688.
Heimer, L. (2000). Basal forebrain in the context of schizophrenia. Brain Research
Review, 31, 205-235.
Heimer, L., Harlan, R. E., Alheid, G. F., Garcia, M. M., & De Olmos, J. (1997).
Substantia innominata: A notion which impedes clinical-anatomical correla^
tions in neuropsychiatric disorders. Neuroscience, 76, 957-1006.
Hengstschlager, M., Van Trotsenburg, M., Repa, C., Marton, E., Hiiber, J. C., &.
Bernaschek, G. (2003). Sex chromosome aberrations and transsexualism. Fertil-
ity and Sterility, 79, 639-640.
Hiort, O. (2000). Neonatal endocrinology of abnormal male sexual differentiation:
Molecular aspects. Hormone Research, 53, 38-41.
Hofman, M. A., & Swaab, D. F. (1989). The sexually dimorphic nucleus of the
preoptic area in the human brain: A comparative morphometric study. Journal
of Anatomy, 164, 55-72.
Holman, S. D., & Hutchison, J. B. (1991). Differential effects of neonatal castration
on the development of sexually dimorphic brain areas in the gerbil. Develop-
mental Brain Research, 61, 147-150.
Honda, K., Yanagimoto, M., Negoro, H., Narita, K., Murata, T., & Higuchi, T.
(1999). Excitation of oxytocin cells in the hypothalamic supraoptic nucleus
by electrical stimulation of the dorsal penile nerve and tactile stimulation of
the penis in the rat. Brain Research Bulktin, 48, 309-313.
Howard, G., Peng, L., & Hyde, J. F. (1997). An estrogen receptor binding site
within the human galanin gene. Endocrinology, 138, 4649—4656.
Hu, S., Pattatucci, A. M. L., Patterson, C., Li, L., Fulker, D. W., Cherny, S. S., et
al. (1995). Linkage between sexual orientation and chromosome Xq28 in males
but not in females. Nature Genetics, 11, 248-256.
Imperato-McGinley, J., Miller, M., Wilson, J. D., Peterson, R. E., Shackleton, C.,
&. Gajdusek, D. C. (1991). A cluster of male pseudohermaphrodites with 5oc-
reductase deficiency in Papua New Guinea. Ciinicai Endocrinology, 34, 293-298.
Imperato-McGinley, J., Peterson, R. E., Gautier, T., & Sturla, E. (1979). Androgens
and the evolution of male-gender identity among male pseudohermaphrodites
with 5a-reductase deficiency. New England Journal of Medicine, 300, 1233-
1237.

Insel, T. R. (1992). Oxytocin—a neuropeptide for affiliation: Evidence from behav-
ioral, receptor autoradiographic, and comparative studies. Psychoneuroendocrin-
ology, 17, 3-35.
Insel, T. R. (1997). A neurobiological basis of social attachment. American Journal
of Psychiatry, 154, 726-735.
Ishunina, T. A., Kruijver, F. P., Balesar, R., &. Swaab, D. F. (2QOO). Differential
expression of estrogen receptor alpha and beta immunoreactivity in the human
supraoptic nucleus in relation to sex and aging. Journal of Clinical Endocrinology
and Metabolism, 85, 3283-3291.
Ishunina, T. A., Salehi, A., Hofman, M. A., & Swaab, D. F. (1999). Activity of
vasopressinergic neurons of the human supraoptic nucleus is age and sex
dependent. Journal of Neuroendocrinology, 11, 251-258.
Ishunina, T. A., Salehi, A., & Swaab, D. F. (2000). Sex- and age-related p75
neurotrophin receptor expression in the human supraoptic nucleus. Neuroendo-
crinology, 374, 243-251.
Ishunina, T. A., &. Swaab, D. F. (1999). Vasopressin and oxytocin neurons of the
human supraoptic and paraventricular nucleus; size changes in relation to age
and sex. Journal of Clinical Endocrinology and Metabolism, 84, 4637-4644.
Ishunina, T. A., & Swaab, D. F. (2002). Neurohyposeal peptides in aging and
Alzheimer's disease. Aging Research Reviews, I, 537-558.
Kallmann, F. J. (1952). Comparative twin study on the genetic aspects of male
homosexuality. Journal of Nervous Mental Diseases, 115, 283-298.
Karama, S., Roch Lecours, A., Leroux, J.-M., Bourgouin, P., Beaudoin, G., Joubert,
S., & Beauregard, M. (2002). Areas of brain activation in males and females
during viewing of erotic film excerpts. Human Brain Mapping 16, 1-13.
Kartha, K. N. B., & Ramakrishna, T. (1996). The role of sexually dimorphic medial
preoptic area of the hypothalamus in the sexual behaviour of male and female
rats. P/vysiological Research, 45, 459-466.
Kindon, H. A., Baum, M. J., &. Paredes, R. J. (1996). Medial preoptic/anterior
hypothalamic lesions induce a female-typical profile of sexual partner prefer-
ence in male ferrets. Hormones and Behavior, 30, 514-527.
Kirkpatrick, M., Smith, C., & Roy, R. (1981). Lesbian mothers and their children:
A comparative survey. American Journal of Orthopsychiatry, 51, 545-551.
Kostoglou-Athanassiou, I., Athanassiou, K., Treacher, D. F., Wheeler, M. J., &
Forsling, M. L. (1998). Neurohypophysial hormone and melatonin secretion
over the natural and suppressed menstrual cycle in premenopausal women.
Clinical Endocrinology, 49, 209-216.
Koutcherov, Y., Mai, J. K., Ashwell, K. W. S., & Paxinos, G. (2002). Organization
of human hypothalamus in fetal development. Journal o/Comparative Neurology,
446, 301-324.
Kruijver, F. P. M., Balesar, R., Espila, A. M., Unmehopa, U. A., & Swaab, D. F.
(2002). Estrogen receptor-a distribution in the human hypothalamus in rela-
64 DICK F. SWAAB
tion to sex and endocrine status, journal of Comparative Neurology, 454, 115-
139.
Kruijver, F. P. M., Balesar, R., Espila, A. M, Unmehopa, U. A., & Swaab, D. F.
(2003). Estrogen-receptor (3 distribution in the human hypothalamus: Similari-
ties and differences with ERa distribution, journal of Comparative Neurology,
466, 251-277.
Kruijver, F. P. M., Fernandez-Guasti, A., Fodor, M., Kraan, E., & Swaab, D. F.
(2001). Sex differences in androgen receptors of the human mamillary bodies
are related to endocrine status rather than to sexual orientation or transsexual-
ity. journal of Clinical Endocrinology and Metabolism, 86, 818-827.
Kruijver, F. P. M., Zhou, J. N., Pool, C. W., Hofman, M. A., Gooren, L. J. G., &.
Swaab, D. F. (2000). Male-to-female transsexuals have female neuron numbers
in a limbic nucleus, journal of Clinical Endocrinology and Metabolism, 85, 2034-
2041.
Lakhdar-Ghazal, N., Kalsbeek, A., & Pevet, P. (1992). Sexual dimorphism and
seasonal variations in vasoactive intestinal peptide immunoreactivity in the
suprachiasmatic nucleus of jerboa (Jaculus orientalis). Neuroscience Letters,
144, 29-33.
Landen, M., Walinder, J., & Lundstrom, B. (1996). Incidence and sex ratio of
transsexualism in Sweden. Acta Psychiatrica Scandinavica, 93, 261-263.
Le Blond, C. B., Morris, S., Karakiulakis, G., Powell, R., & Thomas, P. J. (1982).
Development of sexual dimorphism in the suprachiasmatic nucleus of the rat.
journal of Endocrinology, 95, 137-145.
Lesur, A., Caspar, P., Alvarez, C., & Berger, B. (1989). Chemoanatomic compart-
ments in the human bed nucleus of the stria terminalis. Neuroscience, 32, 181-
194.
LeVay, S. (1991, August 30). A difference in hypothalamic structure between
heterosexual and homosexual men. Science, 253, 1034-1037.
Lilly, R., Cummings, J. L., Benson, D. F., & Frankel, M. (1983). The human Kliiver-
Bucy syndrome. Neurology, 33, 1141-1145.
Liu, Y.-C., Salamone, J. D., & Sachs, B. D. (1997). Impaired sexual response after
lesions of the paraventricular nucleus of the hypothalamus in male rats. Behav'
ioral Neuroscience, I I I , 1361-1367.
Macke, J. P., Hu, N., Hu, S., Bailey, M., King, V. L., Brown, T., et al. (1993).
Sequence variation in the androgen receptor gene is not a common determinant
of male sexual orientation. American journal of Human Genetics, 53, 844-852.
MacLean, P. D., & Ploog, D. W. (1962). Cerebral representation of penile erection.
journal of Neurophysiology, 25, 29-55.
MacNeil, D. J., Howard, A. D., Guan, X., Fong, T. M., Nargund, R. P., Bednarek,
M. A., et al. (2002). The role of melanocortins in body weight regulation:
Opportunities for the treatment of obesity. European journal of Pharmacology,
440, 141-157.

Marlowe, W. B., Mancall, E. L, & Thomas, J. J. (1975). Complete Kliiver-Bucy
syndrome in man. Cortex, 11, 53-59.
Martin, L.J., Powers, R. E., Dellovade, T. L, & Price, D. L. (1991). The bed
nucleus-amygdala continuum in human and monkey. Journal of Comparative
Neurology, 309, 445-485.
Mayer, A., Lahr, G., Swaab, D. F., Pilgrim, C, & Reisert, I. (1998). The Y-chromo-
somal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics,
I, 281-288.
McKenna, K. E. (1998). Central control of penile erection. International Journal of
Impotence Research, 10, S25-S34.
Melis, M. R., Spano, M. S., Succu, S., &. Argiolas, A. (1999). The oxytocin antago-
nist d(CH2)5Tyr(Me)2-Orn8-vasotocin reduces non-contact penile erections in
male rats. Neuroscience Letters, 265L, 171-174.
Melis, M. R., Succu, S., Spano, M. S., & Argiolas, A. (2000). Effect of excitatory
amino acid, dopamine, and oxytocin receptor antagonists on noncontact penile
erections and paraventricular nitric oxide production in male rats. Behavioral
Neuroscience 114, 849-857.
Merari, A., & Ginton, A. (1975). Characteristics of exaggerated sexual behavior
induced by electrical stimulation of the medial preoptic area in male rats.
Meyer, W. J., Webb, A., Stuart, C. A., Finkelstein, J. W., Lawrence, B., & Walker,
P. A. (1986). Physical and hormonal evaluation of transsexual patients: A
longitudinal study. Archives of Sexual Behavior, 15, 121-138.
Meyer-Bahlburg, H. F. L., Ehrhardt, A. A., Rosen, L. R., Gruen, R. S., Veridiano,
N. P., Van, F. H., & Neuwalder, H. F. (1995). Prenatal estrogens and the
development of homosexual orientation. Developmental Psychology, 31, 12-21.
Meyer-Bahlburg, H. F. L., Gruen, R. S., New, M. L, Bell, J. J., Morishima, A.,
Shimshi, M., et al. (1996). Gender change from female to male in classical
congenital adrenal hyperplasia. Hormones and Behavior, 30, 319-332.
Meyers, R. (1961). Evidence of a locus of the neural mechanisms for libido and
penile potency in the septo-fornico-hypothalamic region of the human brain.
Transactions of the American Neurological Association, 86, 81-85.
Meyerson, B. J., Hoglund, U., Johansson, C., Blomqvist, A., &. Ericson, H. (1988).
Neonatal vasopressin antagonist treatment facilitates adult copulatory behavior
in female rats and increases hypothalamic vasopressin content. Brain Research,
473, 344-351.
Miller, B. L., Cummings, J. L., Mclntyre, H., Ebers, G., & Grade, M. (1986).
Hypersexuality or altered sexual preference following brain injury. Journal of
Neurology, Neurosurgery, and Psychiatry, 49, 867-873.
Mitchell, M. D., Haynes, P.J., Anderson, A. B. M., & Turnbull, A. C. (1980).
Oxytocin in human ovulation. Lancet, 2(8196), 704.
Mizusawa, H., Hedlund, P., & Andersson, K.-E. (2002). a-Melanocyte stimulating
hormone and oxytocin induced penile erections, and intracavernous pressure
increases in the rat. Journal of Urology, 167, 757-760.
66 DICK F. SWAAB
Molin-Carballo, A., Munoz-Hoyos, A., Martin-Garcia, J. A., Uberos-Fernandez, J.,
Rodriguez-Cabezas, T., & Acuna-Castroviejo, D. (1996). 5-Methoxytryptophol
and melatonin in children: Differences due to age and sex. Journal of Pineal
Research, 21, 73-79.
Molinoff, P. B., Shadiack, A. M., Earle, D., Diamond, L. E, & Quon, C. Y. (2003).
PT-141: A melanocortin agonist for the treatment of sexual dysfunction. Annah
of the New York Academy of Sciences, 994, 96-102.
Money, J., & Erhardt, A. A. (1972). Man and woman, boy and girl: The differentiation
and dimorphism of gender identity from conception to maturity. Baltimore: Johns
Hopkins University Press.
Money, J., Hampson, J. G., & Hampson, J. L. (1955a). An examination of some
basic sexual concepts: The evidence of human hermaphroditism. Bulletin of
Johns Hopkins Hospital, 97, 301-319.
Money, J., Hampson, J. G., & Hampson, J. L. (1955b). Hermaphroditism: Recom-
mendations concerning assignment of sex, change of sex and psychological
management. Bulletin of Johns Hopkins Hospital, 97, 284-300.
Money, J., Schwartz, M., & Lewis, V. G. (1984). Adult erotosexual status and fetal
hormonal masculinization: 46,XX congenital virilizing adrenal hyperplasia and
46,XY androgen-insensitivity syndrome compared. Psychoneuroendocrinology,
9, 405-414.
Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C., & Qin, K. (1995).
Aromatase deficiency in male and female siblings caused by a novel mutation
and the physiological role of estrogens. Journal of Clinical Endocrinology and
Metabolism, 80, 3689-3698.
Mufson, E. J., Kahl, U., Bowser, R., Mash, D. C., Kordower, J. H., & Deecher, D. C.
(1998). Galanin expression within the basal forebrain in Alzheimer's disease.
Annals of the New York Academy of Sciences, 863, 291-304.
Miiller, D., Roeder, F., & Orthner, H. (1973). Further results of stereotaxis in the
human hypothalamus in sexual deviations. First use of this operation in addic-
tion to drugs. Neurochirurgia, 16, 113-126.
Murphy, M. R., Checkley, S. A., Seckl, J. R., & Lightman, S. L. (1990). Naloxone
inhibits oxytocin release at orgasm in man. Journal of Clinical Endocrinology
and Metabolism, 71, 1056-1058.
Murphy, M. R., Seckl, J. R., Burton, S., Checkley, S. A., & Lightman, S. L. (1987).
Changes in oxytocin and vasopressin secretion during sexual activity in men.
Ochoa, B. (1998). Trauma of the external genitalia in children: Amputation of
the penis and emasculation. Journal of Urology, 160, 1116-1119.
Ozisik, G., Achermann, J. C., & Jameson, J. L. (2002). The role of SF1 in adrenal
and reproductive function: Insight from naturally occurring mutations in hu-
mans. Moiecuiar Genetics and Metabolism, 76, 85-91.
Paredes, R. G., & Baum, M. J. (1995). Altered sexual partner preference in male
ferrets given excitotoxic lesions of the preoptic area/anterior hypothalamus.
Journal of Neuroscience, 15, 6619-6630.

Paredes, R. G., Tzschentke, T., &Nakach, N. (1998). Lesions of the medial preoptic
area/anterior hypothalamus (MPOA/AH) modify partner preference in male
rats. Brain Research, 813, 1-8.
Pfaus, J. G., Kleopoulos, S. P., Mobbs, C. V., Gibbs, R. B., & Pfaff, D. W. (1993).
Sexual stimulation activates c-fos within estrogen-concentrating regions of the
female rat forebrain. Brain Research, 624, 253-267.
Pilgrim, C., & Reisert, I. (1992). Differences between male and female brains:
Developmental mechanisms and implications. Hormone and Metabolic Research,
241, 353-359.
Pillard, R. C., & Bailey, M. (1998). Human sexual orientation has a heritable
component. Human Biology, 70, 347-365.
Poeck, K., & Pilleri, G. (1965). Release of hypersexual behaviour due to lesion in
the limbic system. Acta Neurologica Scandinavica, 41, 233-244.
Punnonen, R., Viinamaki, O., & Multamaki, S. (1983). Plasma vasopressin during
normal menstrual cycle. Hormone Research, 17, 90-92.
Quigley, A. (2002). The postnatal gonadotropin and sex steroid surge: Insights
from the androgen insensitivity syndrome. Journal of Clinical Endocrinology and
Metabolism, 87, 24-28.
Ranee, N. E., Young, W. S., Ill, & McMullen, N. T. (1994). Topography of neurons
expressing luteinizing hormone-releasing hormone gene transcripts in the hu-
man hypothalamus and basal forebrain. Journal of Comparative Neurology,
339, 573-586.
Reiner, W. G. (1996). Case study: sex reassignment in a teenage girl. Journal o/the
American Academy of Child Adolescent Psychiatry, 35, 799-803.
Reiner, W. G. (2002). Gender identity and sex assignments: A reappraisal for the
21st century. Advanced Experiments in Medical Biology, 511, 175-189.
Reiner, W. G., &.Gearhart, J. P. (2004). Discordant sexual identity in some genetic
males with cloacal exstrophy assigned to female sex at birth. New England
Journal of Medicine, 350, 333-341.
Resko, J. A., Perkins, A., Roselli, C. E., Fitzgerald, J. A., Choate, J. V. A., &. Storm-
shak, F. (1996). Endocrine correlates of partner preference behavior in rams.
Biology of Reproduction, 55, 120-126.
Rice, G., Anderson, C., Risch, N., &. Ebers, G. (1999, April 23). Male homosexual-
ity: Absence of linkage to microsatellite markers at Xq28. Science, 284, 665-
667.
Richer, I., & Sigusch, V. (1979). Psychosurgery on sex offenders and sexual 'deviants'
in West Germany. Archives of Sexual Behavior, 8, 523-527.
Roselli, C. E., Abdelgadir, S. E., & Resko, J. A. (1997). Regulation of aromatase
gene expression in the adult rat brain. Brain Research Bulletin, 44, 351-357.
Roselli, C. E., Larkin, K., Resko, J. A., Stellflug, J. N., & Stormshak, F. (2004).
The volume of a sexually dimorphic nucleus in the ovine medial preoptic area/
anterior hypothalamus varies with sexual partner preference. Endocrinology,
145, 478-483.
68 DICK F. SWAAB
Roselli, C. E., & Resko, J. A. (2001). Cytochrome P450 aromatase (CYP19) in the
non-human primate brain: Distribution, regulation, and functional signifi-
cance. Journal of Steroid Biochemistry and Molecular Biology, 79, 247-253.
Sadeghi, M., & Fakhrai, A. (2000). Transsexualism in female monozygotic twins:
A case report. Australian and New Zealand Journal of Psychiatry, 34, 862-864.
Sasano, H., Takahashi, K., Satoh, F., Nagura, H., & Harada, N. (1998). Aromatase
in the human central nervous system. Clinical Endocrinology, 48, 325-329.
Sato, T., Matsumoto, T., Kawano, H., Watanabe, T., Uematsu, Y., Sekine, K., et
al. (2004). Brain masculinization requires androgen receptor function. Proceed'
ings of the National Academy of Sciences, 101, 1673-1678.
Savic, I., Berglund, H., Gulyas, B., & Roland, P. (2001). Smelling of odorous sex
hormone-like compounds causes sex-differentiated hypothalamic activations
in humans. Neuron, 30, 661-668.
Schorsch, E., & Schmidt, G. (1979). Hypothalamotomie bei sexuellen Abwei-
chungen [Hypothalectomy in case of sexual deviations]. Nervenarzt, 50, 689-
699.
Schultz, C., Braak, H., & Braak, E. (1996). A sex difference in neurodegeneration
of the human hypothalamus. Neuroscience Letters, 212, 103-106.
Segarra, G., Medina, P., Domenech, C., Vila, J. M., Martinez-Leon, J. B., Aldasoro,
M., &. Lluch, S. (1998). Role of vasopressin on adrenergic neurotransmission
in human penile blood vessels. Journal of Pharmacology and Experimental Thera-
peutics, 286, 1315-1320.
Simerly, R. B., Gorski, R. A., & Swanson, L. W. (1986). Neurotransmitter specific-
ity of cells and fibers in the medial preoptic nucleus: An immunohistochemical
study in the rat. Journal of Comparative Neurology, 246, 343-362.
Skuse, D. H. (1999). Genomic imprinting of the X-chromosome: A novel mecha-
nism for the evolution of sexual dimorphism. Journal of Laboratory and Clinical
Medicine, 133, 23-32.
Slijper, F. M. E., Stenvert, L. S., Drop, M. D., Molenaar, J. C., & De Muinck Keizer-
Schram, S. M. P. F. (1998). Long-term psychological evaluation of intersex
children. Archives of Sexual Behavior, 27, 125
Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R. M., Specker, B., et
al. (1994). Estrogen resistance caused by a mutation in the estrogen-receptor
gene in a man. New England Journal of Medicine, 331, 1056-1061.
Swaab, D. F. (2002). Gender issues in brain structures and functions and their
relevance for psychopathology. In H. D'haenen, J. A. Den Boer, & P. Willner
(Eds.), Biological psychiatry (pp. 189-209). New York: Wiley.
Swaab, D. F., & Fliers, E. (1985, May 31). A sexually dimorphic nucleus in the
human brain. Science, 228, 1112-1115.
Swaab, D. F., Fliers, E., & Partiman, T. S. (1985). The suprachiasmatic nucleus of
the human brain in relation to sex, age and senile dementia. Brain Research,
342, 37-44.

Swaab, D. F., Gooren, L. J. G., & Hofman, M. A. (1992). The human hypothalamus
in relation to gender and sexual orientation. In D. F. Swaab, M. A. Hofman,
M. Mirmiran, R. Ravid, & F. W. Van Leeuwen (Eds.), Progress in brain research:
Vol. 93. The human hypothalamus in health and disease (pp. 205-215). Amster-
dam: Elsevier.
Swaab, D. F., &. Hofman, M. A. (1984). Sexual differentiation of the human brain:
A historical perspective. In De Vries et al. (Eds.), Progress in brain research:
Vol. 61. Sex differences in the brain: Relation between structure and function (pp.
361-374). Amsterdam: Elsevier.
Swaab, D. F., & Hofman, M. A. (1988). Sexual differentiation of the human hypo-
thalamus: Ontogeny of the sexually dimorphic nucleus of the preoptic area.
Developmental Brain Research, 44, 314-318.
Swaab, D. F., & Hofman, M. A. (1990). An enlarged suprachiasmatic nucleus in
homosexual men. Brain Research, 537, 141-148.
Swaab, D. F., & Hofman, M. A. (1995). Sexual differentiation of the human hypo-
thalamus in relation to gender and sexual orientation. Trends in Neurosciences,
18, 264-270.
Swaab, D. F., Hofman, M. A., & Honnebier, M. B. O. M. (1990). Development of
vasopressin neurons in the human suprachiasmatic nucleus in relation to birth.
Swaab, D. F., Kamphorst, W., Raadsheer, F. C., Purba, J. S., Ravid, R., & Tilders,
F. J. H. (1995). Increased hypothalamo-pituitary-adrenal axis activity is not
pivotal in the pathogenesis of Alzheimer's disease. In K. Iqbal, J. A. Mortimer,
B. Winblad, & H. M. Wisniewski (Eds.), Research advances in Alzheimer's disease
and related disorders (pp. 461-466). New York: Wiley.
Swaab, D. F., Zhou, J. N., Ehlhart, T., & Hofman, M. A. (1994). Development of
vasoactive intestinal polypeptide Z(VIP) neurons in the human suprachi-
asmatic nucleus (SCN) in relation to birth and sex. Developmental Brain
Research, 79, 249-259.
Takahashi, T., Shoji, Y., Shoji, Y., Haraguchi, N., Takahashi, I., & Takada, G.
(1997). Active hypothalamic-pituitary-gonadal axis in an infant with X-linked
adrenal hypoplasia congenita. Journal of Pediatrics, 130, 485-488.
Takano, K., Utsunomiya, H., Ono, H., Ohfu, M., & Okazaki, M. (1999). Normal
development of the pituitary gland: assessment with three-dimensional MR
volumetry. American journal of Neuroradiology, 20, 312-315.
Takeda, S., Kuwabara, Y., & Mizuno, M. (1985). Effects of pregnancy and labor
on oxytocin levels in human plasma and cerebrospional fluid. Erulocrmologia
Japonica, 32, 875-880.
Tatemoto, K., Rokaeus, A., Jornvall, H., McDonald, T.J., & Mutt, V. (1983).
Galanin—A novel biologically active peptide from porcine intestine. Federa-
tion of European Biochemical Societies, 164, 124-128.
Terzian, H., & Dalle Ore, G. (1955). Syndrome of Kliiver and Bucy: Reproduced
in man by bilateral removal of the temporal lobes. Neurology, 5, 373-380.
70 DICK F. SWAAB
Tucker Halpern, C, Udry, J. R., & Suchindran, C. (1998). Monthly measures of
salivary testosterone predict sexual activity in adolescent males. Archives of
Sexual Behavior, 27, 445-465.
Turan, M., E§el, E., Dtindar, M., Candemir, Z., Ba§turk, M., Sofuoglu, S., & Ozkul,
Y. (2000). Female-to-male transsexual with 47.XXX karyotype. Biological Psy*
chiatry,48, 1116-1117.
Turkenburg, J. L., Swaab, D. F., Endert, E., Louwerse, A. L., & Van de Poll, N. E.
(1988). Effects of lesions of the sexually dimorphic nucleus on sexual behaviour
of testosterone-treated female Wistar rats. Brain Research Bulletin, 21, 215-224.
Turner, W. J. (1995). Homosexuality, Type 1: An Xq28 phenomenon. Archives of
Sexual Behavior, 24, 109-134.
Udry, J. R., Morris, N. M., & Kovenock, J. (1995). Androgen effects on women's
gendered behaviour. Journal of Biosocial Science, 27, 359-368.
Uvnas-Moberg, K., Alster, P., Petersson, M., Sohlstrom, A., & Bjorkstrand, E.
(1998). Postnatal oxytocin injections cause sustained weight gain and increased
nociceptive thresholds in male and female rats. Pediatric Research, 43, 344-348.
Uvnas-Moberg, K., Sjogren, C., Westlin, L., Andersson, P. O., & Stock, S. (1989).
Plasma levels of gastrin, somatostatin, VIP, insulin and oxytocin during the
menstrual cycle in women (with and without oral contraceptives). Acta Obstet-
rica et Gynecologica Scandinavica, 68, 165-169.
Valdueza, J. M., Cristante L., Dammann, O., Bentele, K., Vortmeyer, A., Saeger,
W., et al. (1994). Hypothalamic hamartomas: With special reference to gelastic
epilepsy and surgery. Neurosurgery, 34, 949-958.
Van der Beek, E. M., Horvath, T. L., Wiegant, V. M., Van den Hurk, R., & Buijs,
R. M. (1997). Evidence for a direct neuronal pathway from the suprachiasmatic
nucleus to the gonadotropin-releasing hormone system: Combined tracing
and light and electron microscopic immunocytochemical studies. Journal of
Van der Beek, E. M., Wiegant, V. M., Van der Donk, H. A., Van den Hurk, R.,
& Buijs, R. M. (1993). Lesions of the suprachiasmatic nucleus indicate the
presence of a direct VIP containing projection to gonadotropin-releasing hor-
mone neurons in the female rat. Journal ofNeuroendocrinology, 5, 137-144.
Van der Ploeg, L. H. T., Martin, W. J., Howard, A. D., Howard, A. D., Nargund,
R. P., Austin, C. P., et al. (2002). A role for the melanocortin 4 receptor in
sexual function. Proceedings of the National Academy of Sciences, 99, 11381-
11386.
Van Eerdenburg, F. J. C. M., & Swaab, D. F. (1991). Increasing neuron numbers
in the vasopressin and oxytocin containing nucleus of the adult female pig
hypothalamus. Neurosdence Letters, 132, 85-88.
Van Londen, L., Goekoop, J. G., Van Kemper, G. M. J., Frankhuijsen-Sierevogel,
A. C., Wiegant, V. M., Van der Velde, E. A., & De Wied, D. (1997). Plasma
levels of arginine vasopressin elevated in patients with major depression. Neu-
ropsychopharmacology, 17, 284-292.

Vermeulen, A. (1990). Androgens and male senescence. In E. Nieschlag &. H. M.
Behre (Eds.), Testosterone: Action, deficiency, substitution (pp. 629-645). Berlin,
Germany: Springer Verlag.
Walter, A., Mai, J. K., Lanta, L, & Gores, T. (1991). Differential distribution of
immunohistochemical markers in the bed nucleus of the stria terminalis in
the human brain. Journal of Chemical Neuroanatomy, 4, 281-298.
Ward, O. B. (1992). Fetal drug exposure and sexual differentiation of males. In
A. A. Gerall, H. Moltz, &. I. L. Ward (Eds.), Handbook of behavioral neurobiology
(Vol. 11, pp. 181-219). New York: Plenum Press.
Watabe, T., & Endo, A. (1994). Sexual orientation of male mouse offspring prena-
tally exposed to ethanol. Neurotoxicology and Teratology, 16, 25-29.
Weyl, N. (1987). Hormonal influences on sexual inversion: A dual inheritance
model of Proust's homosexuality. Journal of Social and Biological Structures,
10, 385-390.
Wilson, J. D. (1999). The role of androgens in male gender role behavior. Endocrine
Review, 20, 726-737.
Wilson, J. D., Griffin, J. E., & Russell, D. W. (1993). Steroid 5oc-reductase 2 defi-
ciency. Endocrinology Review, 14, 577-593.
Wisniewski, A. B., Migeon, C. J., Meyer-Bahlburg, H. F. L., Gearhart, J. P., Berko-
vitz, G. D., Brown, T. R., & Money, J. (2000). Complete androgen insensitivity
syndrome: Long-term medical, surgical, and psychosexual outcome. Journal of
Clinical Endocrinology and Metabolism, 85, 2664-2669.
Yahr, P., Finn, P. D., Hoffman, N. W., & Sayag, N. (1994). Sexually dimorphic
cell groups in the medial preoptic area that are essential for male sex behavior
and the neural pathways needed for their effects. Ps^choneuroendocrinology,
19, 463-470.
Young, L. J., Wang, Z., & Insel, T. R. (1998). Neuroendocrine bases of monogamy.
Trends in Neurosciences, 21, 71-75.
Zderic, S. A., Canning, D. A., Carr, M. C., Kodman-Jones, C., & Snyder, HMcC
(2002). The CHOP experience with cloacal exstrophy and gender reassign-
ment. Advanced Experiments in Medical Biology, 511, 135-144.
Zhou, J.N., Hofman, M. A., Gooren, L. J. G., & Swaab, D. F. (1995). A sex
difference in the human brain and its relation to transsexuality. Nature,
378, 68-70.
Zhou, J. N., Hofman, M. A., & Swaab, D. F. (1995a). No changes in the number
of vasoactive intestinal polypeptide (VlP)-expressing neurons in the suprachi-
asmatic nucleus of homosexual men; comparison with vasopressin-expressing
neurons. Brain Research, 672, 285-288.
Zhou, J. N., Hofman, M. A., & Swaab, D. F. (1995b). VIP neurons in the human
SCN in relation to sex, age, and Alzheimer's disease. Neurobiology of Aging,
16, 571-576.
Zucker, K. J. (2002). Intersexuality and gender identity differentiation. Journal of
Pediatric Adolescent Gynecology, 15, 3-13.
72 DICK F. SWAAB
Zucker, K. J., Bradley, S. J., & Hughes, H. E. (1987). Gender dysphoria in a child
with true hermaphroditism. Canadian Journal of Psychiatry, 32, 602-609.
Zucker, K. J., Bradley, S. J., Oliver, G., Blake, J., Fleming, S., & Hood, J. (1996).
Psychosexual development of women with congenital adrenal hyperplasia.
Hormones and Behavior, 30, 300-318.
GLOSSARY
Central nucleus of the bed nucleus of the stria terminalis (BSTc): a structure
located between the ventral tip of the lateral ventricle and the anterior commis-
sure. It is involved in many aspects of sexual behavior and is twice as large
in males as in females. This sex difference is reversed in transsexuals. The sex
difference in the BSTc thus seems to parallel gender identity. Many of the
neurons of the BSTc contain the neuropeptide somatostatin as a messenger,
and the BSTc receives a dense network of vasoactive intestinal polypeptide-
containing fibers.
Galanin: a neuropeptide that is present in the SDN-POA neurons. This peptide
induces both female and male types of sexual behavior and influences eating
behavior and sleep. The production of this peptide is regulated by estrogens.
Gamma-amino butyric acid (GABA): the main inhibiting neurotransmitter in the
brain, also present in the SDN-POA.
Infundibular nucleus: the same as the arcuate nucleus in rat. It is the area from
where the menstrual cycle is regulated and a crucial structure for metabolism
and growth.
Interstitial nucleus of the anterior hypothalamus (INAH 1-3): numbered 1-4
(see Figure 3.1). Small hypothalamic cell groups. INAH-1 is the same as the
SDN-POA. The other IN AH cell groups are chemically and functionally
not defined.
Medial mamillary nucleus (MMN): the main component of the mamillary bodies,
crucial for memory. These bodies receive information from the hippocampal
complex by the fornix and transfer this information to the thalamus.
Morphometric analysis: a procedure to estimate—from thin sections under the
microscope—total cell numbers, and so on, in a three-dimensional structure.
The microscope is usually linked to a computer.
Paraventricular nucleus (PVN): the autonomic center of the hypothalamus, con-
taining a large number of different neurons with different peptide content,
different fields of termination, and different functions. The oxytocin and vaso-
pressin neurons of the PVN are involved in affiliation, including pair bonding,
parental care, territorial aggression, and aspects of sexual behavior, including
penile erections.
Sexually dimorphic nucleus of the preoptic area (SDN-POA): a structure in the
anterior hypothalamus that in young adults is about twice as large in males
as in females. The medial preoptic area (mPOA) is involved in penile erection,

mounting, intromission, ejaculation, and sexual orientation. In the literature
this area is also called INAH-1, or intermediate nucleus.
Substance-P: a neuropeptide involved, for example, in pain perception. It is also
present in small amounts in the SDN-POA.
Suprachiasmatic nucleus (SCN): the biological clock, situated on top of the
crossing of the optic nerves. It regulates all day/night rhythms and appears to
be twice as large in homosexual males as in heterosexual males. A major
neuropeptide in the SCN is vasopressin.
Supraoptic nucleus (SON): situated on top of the optic nerve. It is responsible
for the major part of circulating vasopressin. Vasopressin not only acts as
antidiuretic hormone on the kidneys but is also involved in aspects of
reproduction.
Thyrotropin-releasing hormone (TRH): a neuropeptide that is produced in the
PVN and released into the portal capillaries in the median eminence and
regulates, via the pituitary gland, the function of the thyroid. It also has central
functions, such as metabolism and temperature regulation. It influences mood
and is also present in the SDN-POA.
Vasoactive intestinal polypeptide (VIP): a peptide produced by some neurons as
a chemical messenger. A dense network of VIP fibers innervates the BSTc.
74 DICK F. SWAAB
THE CENTRAL CONTROL AND
PHARMACOLOGICAL MODULATION
OF SEXUAL FUNCTION
KEVIN E. McKENNA
In this review, I describe the central nervous system pathways that

control sexual function. The peripheral control of sexual organs, especially
the penis, has been extensively reviewed and is not reiterated here (Anders-
son & Wagner, 1995; De Groat & Booth, 1993; De Groat & Steers, 1990).
I also review recent work on the pharmacological manipulation of various
sexual responses. Most of the work reviewed has been performed in experi-
mental animals, especially in rats. Therefore, considerable caution is needed
in making conclusions of the effects of pharmacological agents on sexual
function in humans. Furthermore, a large proportion of research has been
devoted to studying penile erection in males. Functions such as ejaculation
and female genital arousal have received considerably less attention. Some
general conclusions can be drawn concerning the neural control of sexual
function. Sexual reflexes are largely generated by neural pathways within
the spinal cord. These can be activated by genital sensory stimulation.
They are also under descending modulation from supraspinal centers. Both
inhibitory and excitatory pathways have been identified. The excitatory
pathways are capable of activating sexual responses even in the absence
75
of genital stimulation, such as in the case of sexual arousal induced by
mental imagery.
SPINAL INNERVATION OF THE SEXUAL ORGANS
In this section I discuss the various mechanisms of the nervous system

that control sexual organ functioning through the spinal cord. First I discuss
motor, sensory, and interneuron mechanisms, then I focus on spinal reflexes
and the role of different parts of the brain.
Motor
Thorough reviews of the innervation of the pelvic organs have been

published (Bell, 1972; Janig & McLachlan, 1987). Pelvic innervation has
been most extensively studied in the rat. In the rat, the autonomic innerva-
tion of the pelvic organs is provided primarily by the major pelvic ganglion
(Langworthy, 1965; Purinton, Fletcher, &. Bradley, 1976). This is a triangular
structure located on the lateral surface of the cervix in females and the
lateral lobe of the prostate in males. Damage to this ganglion, during prostate
surgery in men and hysterectomy in women, can lead to sexual dysfunction
(Hasson, 1993; Walsh & Donker, 2002). It is a mixed ganglion, containing
both sympathetic and parasympathetic postganglionic neurons. Postgangli-
onic fibers from the ganglion innervate the pelvic organs, including the
bladder, urethra, accessory sex glands, vagina, uterus, clitoris, and penis.
The cavernous nerve is the largest nerve issuing from the pelvic ganglion and
provides the vasodilatory innervation to the penis and clitoris (Langworthy,
1965). After nearly a century of research, the neurotransmitter mediating
the vasodilation of the penis and clitoris elicited by cavernous nerve activa-
tion has been identified as nitric oxide (Andersson & Wagner, 1995; Burnett,
Lowenstein, Bredt, Chang, & Snyder, 1992; Park et al., 1997).
Application of tracers to the rat pelvic nerve has been used to label
parasympathetic preganglionic neurons in the sacral parasympathetic nu-
cleus in the lumbosacral segments of the spinal cord (Hancock & Peveto,
1979b; Nadelhaft & Booth, 1984). These neurons were located in a compact
column in the lateral intermediate gray matter. This is on the border between
the gray matter (nerve cells) and white matter (nerve fibers) of the spinal
cord. No differences were noted in the number or distribution of labeled
cells in males or females. Sympathetic preganglionic neurons in the thoraco-
lumbar segments of the spinal cord were labeled following application of
tracer to the hypogastric nerve (Hancock & Peveto, 1979a; Nadelhaft &
McKenna, 1987). The preganglionic neurons were found bilaterally in the
76 KEVIN E. McKENNA
intermediolateral cell column and in the medial central gray, dorsal to the
central canal.
The pudendal nerve innervates the striated perineal muscles, the exter-
nal anal and urethral sphincters, and the ischiocavernosus and bulbospongio-
sus muscles (Breedlove & Arnold, 1981; Jordan, Breedlove, & Arnold, 1982;
McKenna & Nadelhaft, 1986; Schr0der, 1980). The pudendal motoneurons
are located in the lumbar spinal cord. The number of motoneurons is sexually
dimorphic, with considerably more motoneurons in the male compared with
the female. This directly reflects the dimorphism of the ischiocavernosus
and bulbospongiosus muscles, which are prominent in the male and very
small in the female rat.
Sensory
Anatomical studies have shown that sensory fibers from the pudendal,
pelvic, and hypogastric nerves innervate pelvic organs. The pudendal nerve
provides sensory innervation for the perineum, penis or clitoris, and urethra.
In the female, the size and sensitivity of the pudendal perineal innervation
are increased by estrogen (Adler, Davis, & Komisaruk, 1977; Komisaruk,
Adler, & Hutchinson, 1972; Kow & Pfaff, 1973). The pudendal sensory
innervation plays an essential role in sexual reflexes.
Pelvic nerve sensory fibers innervate the internal sexual organs. Indi-
vidual fibers innervate only a single pelvic organ. Most vaginal and uterine
afferent fibers appear to be unmyelinated (small fibers without an insulating
sheath). In the female, the pelvic nerve innervation has been shown to be
crucial for the induction of pregnancy or pseudopregnancy due to mating
or cervical stimulation (Carlson & De Feo, 1965; Kollar, 1953). The role
of pelvic nerve sensory innervation of the male sex organs is unclear. There
are relatively few sensory fibers in the hypogastric nerve of the rat (Nadelhaft
& McKenna, 1987). However, these neurons have been shown to be impor-
tant for the pain sensation from the uterus (Berkley, Robbins, & Sato, 1987).
The functions of hypogastric sensory neurons in the male are unknown.
The afferents from the pelvis terminate primarily in the medial portions
of the dorsal horn and in the medial central gray matter of the lumbosacral
spinal cord (McKenna & Nadelhaft, 1986; Nadelhaft & Booth, 1984; Nadel-
haft & McKenna, 1987). The pudendal afferents have an almost exclusively
medial distribution. Visceral pelvic afferents terminate both medially and
in the lateral edge of the gray matter, in the vicinity of the sacral parasympa-
thetic nucleus.
It has been reported recently that vagal fibers may convey sensory
information from female pelvic organs to sensory nuclei in the brainstem
(Komisaruk, Gerdes, & Whipple, 1997; Whipple, Richards, Tepper, &
Komisaruk, 1995). The vagal pathway remains functional after spinal cord
CONTROL AND MODULATION OF SEXUAL FUNCTION 77

transaction and may account for the menstrual cramping, analgesia, and
orgasm reported in women with complete spinal cord transections.
Sensory innervation of the genitals is provided primarily by afferent
fibers in the pudendal nerve. It has recently been reported that sensory
fibers in the skin of the penis contain receptors for melanocortin (Van der
Ploeg et al., 2002). Melanocortin is a peptide that has roles as a pituitary
hormone and a neurotransmitter. It is being investigated for use in the
treatment of sexual dysfunction (see below). Pudendal nerve afferents termi-
nate in the medial portions of the dorsal horn and in the central gray matter
(McKenna & Nadeihaft, 1986).
Interneurons
Interneurons relevant to sexual function have been located by neuro-

physiological and anatomical studies. Neurons activated by stimulation of
the pudendal nerve or by perineal and pelvic visceral stimulation were
located in the medial portions of the lumbosacral spinal gray (Fedirchuk,
Song, Downie, &. Shefchyk, 1992; Honda, 1985). Spinal interneurons related
to pelvic function have been identified by a different technique. Strong
activation of neurons often causes expression of the immediate early gene,
C'fos, and its gene product Fos (Sagar, Sharp, & Curran, 1988). Stimulation
of genital afferents resulted in labeled neurons in the medial dorsal horn,
the central gray commissure, and the region of the intermediolateral cell
column (a small nucleus at the lateral edge of the gray matter), consistent
with the distribution of pelvic sensory terminals. The distribution of inter-
neurons was similar in males and females (Birder, Roppolo, ladarola, &
de Groat, 1991; Lee & Erskine, 1996; Rampin, Bernabe, & Giuliano,
1997).
The use of viral tracing has been used to address the question of pelvic
interneurons. Viruses, such as the pseudorabies virus, are picked up by nerve
terminals near the injection site, retrogradely transported to the neuronal
cell body, replicated, and picked up by nerve terminals presynaptic to the
infected neurons (Card et al., 1993; Kuypers & Ugolini, 1990). Similar
patterns of labeling were observed following injection into the penis, clitoris,
uterus, and striated perineal muscles (Marson, 1995; Marson & McKenna,
1996; Marson, Platt, & McKenna, 1993; Papka et al., 1995; Papka, Williams,
Miller, Copelin, & Puri, 1998; Tang, Rampin, Giuliano, & Ugolini, 1999).
The majority of labeled neurons in the spinal cord were located in the
central gray region of the spinal cord and near the intermediolateral cell
column. These studies using different techniques all indicated that pelvic
and sexual reflexes are dependent on spinal neurons in the central gray
region of the lumbosacral segments.
78 KEVIN E. McKENNA
The interneurons mediating ejaculation have been identified recently.
Using neuroanatomical and behavioral techniques, a group of neurons in
the central gray of spinal segments L3 and L4 was identified. When lesioned,
the rats were unable to ejaculate, in copulatory testing, with no other sexual
deficits (Truitt & Coolen, 2002). Note that these neurons were a discrete
cluster of cells located within the larger pool of interneurons previously
identified. Perhaps, additional pools of interneurons mediating other sexual
and pelvic functions will be similarly identified.
Spinal Reflexes
Spinal reflexes, under supraspinal control, generate most sexual

functions. Sexual reflexes are largely activated by pudendal afferents. One
such reflex is the bulbocavernosus reflex. This reflex is a polysynaptic
response seen in males and females elicited by light touch of the penis
or clitoris. This stimulation of pudendal sensory fibers activates pudendal
motoneurons to contract the striated perineal muscles (Bors & Blinn,
1959; McKenna & Nadelhaft, 1989; Rattner, Gerlaugh, Murphy, &
Erdman, 1958; Vodusek, 1990). This reflex could be the basis for some
sexual responses. For example, stimulation of the clitoris could lead to the
development of the orgasmic platform (contraction of the circumvaginal
muscles). In males, this reflex would also lead to contraction of the
ischiocavernosus and bulbospongiosus muscles, which enhances penile
erection. Stimulation of the clitoris and penis causes an inhibition of
bladder activity by inhibition of pelvic nerve activity to the bladder and
an increase in hypogastric nerve activity to the bladder neck. This
inhibits the detrusor muscle of the bladder and contracts the bladder
neck (Erlandson, Fall, & Carlsson, 1977; Lindstrom, Fall, Carlsson, &
Erlandson, 1983). These reflexes strengthen urinary continence during
sexual arousal and prevent retrograde ejaculation. Stimulation of the
pudendal nerve sensory fibers also evokes long latency discharges in the
cavernous nerve, indicating a polysynaptic reflex (Steers, Mallory, & de
Groat, 1988). Stimulation of the pudendal penile sensory innervation
also results in increases in intracavernous pressure (Bernabe, Rampin,
Giuliano, & Benoit, 1995; Rampin et al. 1997. The mechanisms underlying
female sexual responses remain to be elucidated directly.
Evidence indicates that ejaculation or sexual climax is also a spinal
level reflex. Following complete spinal cord injury, women are still able to
experience orgasm (Sipski, Alexander, & Rosen, 1985) and men are able
to ejaculate (Bors &Comarr, 1960; Brindley, 1986b). In anesthetized, acutely
spinalized male and female rats, genital stimulation gives rise to a response
that resembles climax in humans: rhythmic contractions of the striated

perineal muscles and vaginal and uterine contractions in females and penile
erection and ejaculation in males (McKenna, Chung, & McVary, 1991).
This climaxlike response also includes strong activation of the cavernous
nerve, driven by both hypogastric and pelvic nerve preganglionic activity.
Medulla and Pons
A descending inhibitory control of spinal sexual reflexes has long been

known (Beach, 1967). One site, nucleus paragigantocellularis (nPGi), has
been identified in males as important in inhibitory control of spinal sexual
reflexes. This brainstem nucleus is located in the ventral part of the rostral
portion of the medulla. Neurons in the nPGi receive genital sensory informa-
tion in males and females (Hubscher & Johnson, 1996; Rose, 1990). Axons
from the nPGi project to pelvic efferent neurons and intemeurons in the
lumbosacral spinal cord (Marson & McKenna, 1990). Neurons in this area
are transneuronally labeled following virus injection into the penis (Marson
et al., 1993), the clitoris (Marson, 1995), and perineal muscles (Marson &
McKenna, 1996; Tang et al., 1999). Transection of the spinal cord eliminates
a tonic descending inhibition of spinal sexual reflexes. Lesions of this nucleus
are as effective as spinal transection for eliminating the inhibition (Marson
& McKenna, 1990). Chronic lesions of the nPGi facilitated ex copula penile
reflexes (Marson, List, & McKenna, 1992). Ex copula erections are a type
of erection seen in restrained, unanesthetized rats, in response to retraction
of the prepuce of the penis. Male copulatory behavior was enhanced after
chronic nPGi lesions, further indicating an inhibitory role for this nucleus
(Yells, Hendricks, & Prendergast, 1992). Over 80% of the spinally projecting
neurons in the nPGi stain positively for serotonin. Further, serotonin applied
to the spinal cord inhibits spinal sexual reflexes (Marson & McKenna,
1992). The serotonergic inhibition of sexual reflexes by the nPGi is a possible
substrate for the high incidence of orgasmic dysfunction seen with the
use of selective serotonin reuptake inhibitor (SSRI) antidepressants, which
elevate brain serotonin levels (Lane, 1997; Modell, Katholi, Modell, &
DePalma, 1997). The serotonergic receptor subtype mediating the inhibition
is unknown. Serotonergic projections to lumbosacral cord from the brainstem
nuclei raphe pallidus, magnus, and parapyramidal region have been demon-
strated (Du, 1989; G. Holstege, Kuypers, & Boer, 1969; J. C. Holstege,
1987; Loewy & McKellar, 1981; Martin, Vertes, & Waltzer, 1985). The
functional roles of these serotonergic pathways are not known. The purpose
of the tonic inhibition of sexual reflexes is unknown. It may be suggested
that it serves to suppress sexual responses to incidental genital stimuli.
A number of other brainstem nuclei have been shown to project to
relevant areas in the lumbosacral spinal cord, but their functional role in
80 KEVIN E. McKENNA
sexual response is unknown. There are significant noradrenergic projections
from the A5 catecholaminergic cell group and from locus ceruleus (Loewy,
McKellar, & Saper, 1979; Nygren & Olson, 1977). These provide a dense
innervation of pudendal motoneurons, sympathetic and parasympathetic
preganglionic neurons, and interneurons (Kojima et al., 1985; Schr0der &
Skagerberg, 1985). These noradrenergic nuclei are also consistently labeled
following pseudorabies virus injection into sexual organs (Marson, 1995;
Marson & McKenna, 1996; Marson et al., 1993; Tang et al., 1999).
Barrington's nucleus in the parabrachial complex of the pons, also
called the pontine micturition center, plays a key role in the descending
control of bladder and sphincter reflexes (Barrington, 1925; De Groat &
Steers, 1990; G. Holstege, Griffiths, De Wall, & Dalm, 1986; Kuru, 1965).
In addition, Barrington's nucleus has also been shown to be involved in
defecation reflexes and straining responses related to defecation and parturi-
tion (Fukuda & Fukai, 1986a, 1986b, 1988; Fukuda, Fukai, Yamane, &.
Okada, 1981). This nucleus has also been transneuronally labeled following
injection of viral tracers into the penis, clitoris, and the ischiocavernosus
and bulbospongiosus muscles (Marson, 1995; Marson & McKenna, 1996;
Marson et al., 1993). These findings suggest that Barrington's nucleus has
an important role in the control of several pelvic functions, including
sexual function.
Midbrain
In the midbrain, the periaqueductal gray is known to be an important

area for the control of homeostatic functions and motivated behaviors,
including sexual function. It has extensive connections with all of the
brainstem sites just discussed, including the nPGi (Bandler &. Shipley, 1994;
Van Bockstaele, Pieribone, & Aston-Jones, 1989), and has connections
with many hypothalamic sites involved in sexual function (Behbehani,
1995; Simerly & Swanson, 1986, 1988). A high concentration of androgen
receptors has also been identified in this region (Greco, Edwards, Michael,
& Clancy, 1996). Stimulation and recording studies and c-fos experiments
have provided evidence that the ventral tegmental field of the midbrain
has an important role in transmitting genital sensory signals to diencephalic
structures (Baum &. Everitt, 1992; Rose, 1990; Shimura & Shimokochi,
1991). Neurons in this midbrain are labeled following viral injection into
the penis, clitoris, uterus, and perineal muscles (Marson, 1995; Marson &
McKenna, 1996; Marson et al., 1993; Papka et al., 1998; Tang et al., 1999).
Midbrain lesions have been shown to produce major sexual deficits (Barfield,
Wilson, & McDonald, 1975; Brackett & Edwards, 1984; Brackett, luvone,
& Edwards, 1986; T. K. Clark, Caggiula, McConnel, & Antelman, 1975).

Hypothalamus
The medial preoptic area (MPOA) and adjacent regions of the hypo-
thalamus has long been considered necessary for the control of sexual behav-
ior. Lesions of neurons in the MPOA disrupt copulatory behavior in every
vertebrate species examined to date (Hart & Leedy, 1985; Meisel & Sachs,
1994; Rose, 1990). Male sexual behavior is activated by electrical or chemical
stimulation of this area in conscious animals (Davidson, 1966; Malsbury,
1971; Merari & Ginton, 1975) and can elicit sexual responses in anesthetized
animals (Giuliano et al., 1996; Marson & McKenna, 1994). Neurons in
the MPOA contain androgen receptors (Sar & Stumpf, 1975), and implanta-
tion of testosterone into the MPOA restores sexual behavior in castrated
animals (Davidson, 1966). The MPOA has extensive connections with
widespread areas of the limbic system and brainstem (Simerly & Swanson,
1986, 1988).
Following lesions of the MPOA, male copulatory behavior is severely
impaired in animals. Despite this, the animals retain their capacity to have
erection and ejaculation, and they retain their sexual motivation. In an
assessment of sexual motivation using a paradigm in which rats pressed a
bar to gain access to estrous female rats, the MPOA rats continued to be
motivated to have access to the female rats (Everitt & Stacey, 1987).
Following lesions of the MPOA in monkeys, copulatory behavior was se-
verely impaired. However, lesioned male monkeys also continued to bar
press for female monkeys and continued to masturbate to ejaculation (Slimp,
Hart, & Goy, 1975). Thus, it appears that the MPOA does not generate
sexual behavior but is important for integrating sensory and hormonal cues
related to sexual behavior.
The paraventricular nucleus (PVN) of the hypothalamus appears to
be a crucial site for the control of sexual function. Neurons in this area are
activated by genital sensory stimulation (Yanagimoto, Honda, Goto, &
Negoro, 1996). In turn, neurons in the parvocellular division of the PVN
project to multiple levels of the spinal cord, including direct projections to
pelvic autonomic and somatic efferents (Cechetto & Saper, 1988; Saper,
Loewy, Swanson, & Cowan, 1976; Wagner & Clemens, 1991). The PVN
receives an extensive input from the MPOA (Simerly & Swanson, 1988).
The lumbosacral projection is mediated in part by oxytocin neurons (Tang,
Rampin, Galas, Facchinetti, & Giuliano, 1998; Veronneau-Longueville et
al., 1999; Wagner & Clemens, 1993). The PVN was consistently labeled
after pseudorabies virus injection into the penis, clitoris, and the penile
muscles (Marson, 1995; Marson &. McKenna, 1996; Marson et al., 1993).
Stimulation of the PVN elicited seminal discharge in unanesthetized rats
(Van Dis & Larsson, 1970) and erection in anesthetized rats (Chen, Chan,
82 KEVIN E. McKENNA
Chang, & Chan, 1997). Lesions of the PVN caused disruption of seminal
emission in copulatory testing in rats (Ackerman, Lange, & Clemens, 1997).
Forebrain
The medial portion of the amygdala is a crucial region for sexual

behavior. Lesions of the amygdala give rise to disruption in sexual behavior,
particularly aspects of sexual motivation (Everitt, Cador, & Robbins, 1989).
The hypersexuality induced by the large lesions reported by Kluver and
Bucy (1939) are likely due to the removal of inhibitory control by pyriform
cortex that is destroyed in such lesions and not due to damage to the
amygdala. Neurons in the medial amygdala are labeled with c-fos following
copulatory behavior in both males and females (Baum & Everitt, 1992;
Coolen, Peters, & Veening, 1996; Tetel, Getzinger, & Blaustein, 1993).
Forebrain regions involved in female sexual function have largely been
identified on the basis of Fos staining in copulatory tests and viral staining.
Medial amygdala, bed nucleus of the stria terminalis, and some other regions
are most consistently identified (Coolen et al., 1996; Erskine, 1993; Papka
et al., 1998; Tetel et al., 1993; Veening & Coolen, 1998). The Fos labeling
in these regions is strongly affected by vaginocervical stimulation during
copulation.
PHARMACOLOGY OF SEXUAL FUNCTION
Because of the extensive role of the central nervous system, and there-
fore of neurons, in sexual activity, neurological pharmacological agents have
a strong effect on sexual function. This effect varies from drug to drug, and
sometimes from species to species. In the rest of the chapter, I elucidate
the studies of these various drugs and their effects on sexual function.
Serotonin
There is an extensive serotonergic innervation of most of the brain

and spinal sites involved in the control of sexual function (Bancila et al.,
1999; Loewy & McKellar, 1981; Marson & McKenna, 1992; Skagerberg &
Bjorklund, 1985; Steinbusch, 1981; Tang et al., 1998). It is generally agreed
that in large part, serotonin exerts an inhibitory effect on sexual function
(Bitran & Hull, 1987). Decreased serotonin levels, by inhibition of its
synthesis or by lesions of serotonergic neurons, resulted in enhancement of
sexual function (Kondo, Yamanouchi, & Arai, 1993; Marson et al., 1992;
Mclntosh & Barfield, 1984; Yells et al., 1992). In contrast, administration

of serotonin or drugs that increase serotonin levels inhibited sexual function
(Ahlenius et al., 1981; Marson & McKenna, 1992; Svensson & Hansen,
1984; Szele, Murphy, & Garrick, 1988). The major effect of serotonin
appears to be an inhibition of ejaculation or sexual climax. This is the
primary sexual side effect seen with SSRI antidepressants, which increase
serotonin levels (Lane, 1997; Modell et al., 1997). An inhibition of ejacula-
tion in copulatory testing in rats has been noted (Svensson & Hansen,
1984), and climaxlike sexual reflexes were inhibited by serotonin (Marson
& McKenna, 1992).
Thirteen serotonin receptor subtypes have been identified (Barnes &
Sharp, 1999; Gerhardt &. van Heerikhuizen, 1997). The receptor subtypes
on the various neurons involved in the control of sexual function have not
been identified. The 1 A, IB, 2A, and 2C receptor subtypes have been found
in the spinal cord (Marlier, Teilhac, Cerruti, & Privat, 1991; Ridet, Tamir,
& Privat, 1994; Thor, Nickolaus, & Helke, 1993). The 2C receptor has
been identified with neuroanatomical techniques on lumbosacral neurons
specifically related to the control of penile erection (Bancila et al., 1999).
The functional role of these receptors is not entirely clear. Drugs, which
have actions at the 2C receptor, have been found to facilitate erection in
rats. l-(3-Chlorophenyl)-piperazine (m-CPP) andN-trifluoromethylphenyl-
piperazine (TFMPP) are partial agonists at 2C receptors as well as 2A
receptor antagonistic actions (Barnes & Sharp, 1999). These induce erection
and firing in the cavernous nerve; however, they also inhibit ejaculation
and some aspects of sexual behavior (Aloi, Insel, Mueller, & Murphy, 1984;
Berendsen & Broekkamp, 1987; Berendsen, Broekkamp, & van Delft, 1991;
Berendsen, Jenck, & Broekkamp, 1990; Millan, Peglion, Lavielle, & Perrin-
Monneyron, 1997; Pomerantz, Hepner, & Wertz, 1993; Steers & de Groat,
1989; Szele et al., 1988). Another 2C agonist, RSD 992, induced erections
(Hayes, Doherty, Hanson, Gorzalka, & Adaikan, 2000). These data suggest
that 2C receptors in the spinal cord may facilitate erections. It has also been
hypothesized that 2C receptors may be inhibitory to ejaculation (Waldinger,
Berendsen, Blok, Olivier, & Holstege, 1998).
A serotonin 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tet-
ralin (8-OH DP AT), has been studied extensively for its effects in sexual
function (Bitran & Hull, 1987). This drug has complex effects on sexual
behavior. Generally, it has inhibitory effects on erection but greatly facili-
tates ejaculation (Ahlenius et al., 1981; Fernandez-Guasti, Escalante, Ahlen-
ius, Hillegaart, & Larsson, 1992). This drug also facilitated a climaxlike reflex
in anesthetized rats (Carro-Juarez & Rodriguez-Manzo, 2001). However, the
specificity of the action of this drug is in question, because its effects on
male rat sexual behavior are blocked by antagonists of dopamine D2 receptors
and not serotonergic 1A antagonists (Matuszewich et al., 1999). However,
a more selective 1A agonist also reduced ejaculatory latency (Foreman et
84 KEVIN E. McKENNA
al., 1994). It is clear that further research is needed to clarify the role of
serotonin 1A receptors in sexual function.
Trazodone is an antidepressant that is pharmacologically different from
the SSRIs. Its major metabolite, m-CCP, is an agonist at serotonin 2C
receptors and antagonist at 2A receptors (Barnes & Sharp, 1999; Monsma,
Shen, & Ward, 1993). mCPP induces erection in rats and increases the
neural activity of the cavernous nerve (Steers & de Groat, 1989). The
mode of action of trazodone in depression is not fully understood; it
has a marked sedative action. Trazodone has been associated with cases of
priapism (prolonged, painful erection) in men (Azadzoi, Payton, Krane, &
Goldstein, 1990) and clitoral priapism in women (Pescatori et al., 1993).
It has been shown to increase nocturnal tumescence in men (Saenz de
Tejada et al., 1991). The site and mechanism of its sexual side effects are
not known.
Adverse sexual side effects are commonly seen with SSRI antidepres-
sants (Lane, 1997; Modell et al., 1997). The most common effect is to delay
or inhibit ejaculation in men and orgasm in women. These drugs increase
serotonin levels in the brain; however, their pharmacology is complex, and
many neurotransmitter systems are affected by them. This effect of SSRIs
is now being examined for their use in the treatment of premature ejaculation
(Waldinger, 2002). The rationale is that at an appropriate dose, ejaculation
can be delayed but not totally inhibited in these patients.
Dopamine
The medial preoptic area and PVN are extensively innervated by

dopaminergic neurons of the incertohypothalamic pathway (Bjorklund,
Lindvall, & Nobin, 1975). There is also a dopaminergic innervation of the
lumbosacral spinal cord from diencephalic dopaminergic cells (Skagerberg,
Bkorklund, Lindvall, & Schmidt, 1982; Skagerberg & Lindvall, 1985). Thus,
dopamine is anatomically organized to modulate the expression of sexual
function. Numerous pharmacological studies in animals and humans support
this conclusion. In general, dopaminergic agonists facilitate several aspects
of sexual function, from erection, ejaculation, female sexual arousal, and
sexual motivation.
The sexual effects of dopamine seem to involve both the dopaminergic
Dl and D2 receptors, acting in the medial preoptic area and the PVN (Hull,
1995). In the MPOA of male rats, there was a consistent rise in dopamine
release prior to copulation (Hull, Du, Lorrain, & Matuszewich, 1995). This
release was anatomically restricted and specific to sexual stimuli. The release
of dopamine in the MPOA can be mimicked by micro injections of dopamin-
ergic agonists. Microinjection of apomorphine, a nonselective D1/D2 recep-
tor agonist, increased the rate and efficiency of copulation and facilitated

erections (Bazzett et al., 1991; Hull et al., 1986; Hull et al., 1992). Injection
of dopaminergic antagonists into the MPOA decreased the number of penile
reflexes (Pehek, Thompson, & Hull, 1988a; Warner et al., 1991). Injection
of apomorphine into the PVN, but not the MPOA, enhanced seminal
emission. Results have been presented that indicate that Dl receptor stimula-
tion increases erections and D2 stimulation promotes ejaculation (Hull,
1995). In contrast, following micro injection in the PVN, it appears that
D2 rather than Dl receptors primarily facilitate erections (Melis, Argiolas,
& Gessa, 1987). The proerectile effect of dopamine injected into the PVN
was enhanced by administration of selegiline, a drug that inhibits the degra-
dation of dopamine (Allard et al., 2002). These results indicate that dopa-
minergic stimulation of the hypothalamus facilitates male sexual responses.
Note, however, that contrary to these results in rats, rhesus monkeys did
not respond to apomorphine, indicating possible species differences in the
dopaminergic control of sexual function (Chambers & Phoenix, 1989).
In the male, the excitatory effect of paraventricular dopaminergic
stimulation is mediated in part by oxytocin. Oxytocinergic cell bodies in the
PVN receive dopaminergic innervation (Buijs, 1978; Lindvall, Bjorklund, &
Skagerberg, 1984). Penile erection induced by apomorphine can be blocked
by oxytocin receptor antagonists (Argiolas, Melis, Vargiu, & Gessa, 1987;
Melis, Argiolas, &. Gessa, 1989). In contrast, penile erections were induced
by injection of oxytocin into the PVN, and these were not blocked by
dopamine receptor antagonists (Melis et al., 1989). These results suggest
that dopamine stimulates oxytocinergic neurons in the PVN, which then
cause the erectile response.
Dopamine also appears to exert a facilitatory effect on sexual responses
at the spinal level. Intrathecal injection of apomorphine at the lumbosacral
facilitated ejaculation, although it suppressed ex copula erections and slowed
the rate of copulation (Pehek, Thompson, & Hull, 1989a, 1989b). In anes-
thetized rats, intrathecal injection of apomorphine evoked erection in both
normal and spinalized rats (Giuliano et al., 2002).
The role of dopamine in female sexual function is less clear. Dopamine
in the MPOA is increased by estrogen and progesterone administration in
ovariectomized female rats, which induces receptivity. Dopamine further
increased when copulation began (Matuszewich, Lorrain, & Hull, 2000).
Sexual receptivity, as measured by the lordosis quotient, was increased by
administration of apomorphine or D2 agonists (Foreman & Hall, 1987;
Hamburger-Bar & Rigter, 1975). Preceptive behavior was also increased by
D2 agonists (Everitt, Fuxe, Hokfelt, & Jonsson, 1975). The role of dopamine
on female genital arousal or sexual climax has not been investigated. In
humans, data suggest that dopamine increases sexual motivation or desire.
Dopaminergic agents used for the treatment of Parkinsonism sometimes
induce increases in sexual desire (Courty, Durif, Zenut, Courty, & Lavarenne,
86 KEVIN E. McKENNA
1997; Uitti et al., 1989). However, this may be a rare finding (Goodwin,
1971). There are anecdotal reports that cocaine and amphetamine, which
increase dopamine levels, may be aphrodisiac. However, chronic use of
stimulants is associated with severe sexual dysfunction, including anorgasmia
and lack of sexual desire (Miller & Gold, 1988).
The effects of apomorphine on male sexual function in animals have led
to the development of apomorphine as a treatment for erectile dysfunction in
men. Apomorphine is able to induce erection in normal (Lai, Ackman,
Thavundayil, Kiely, & Etienne, 1998) and impotent men (Lai et al., 1987;
Segraves, Bari, Segraves, & Spirna, 1991). No effect of apomorphine was
noted on libido (Lai et al., 1984; Julien & Over, 1984). However, apomor-
phine can cause significant side effects, including nausea, vomiting, drowsi-
ness, flushing, and dizziness (Lai et al., 1984; Segraves et al., 1991). A
sublingual preparation designed to minimize the side effects has been ap-
proved in Europe for the treatment of erectile dysfunction (Heaton, 2001).
Noradrenaline
Noradrenergic neurons from the A5 region, the locus ceruleus, and

subceruleus project to the nuclei in the spinal cord involved in erection
(Schr0der & Skagerberg, 1985). Generally, it appears that increased norad-
renergic activity stimulates, and decreased noradrenergic activity inhibits,
sexual function (Bitran & Hull, 1987). Hypothalamic nuclei are also targets
of noradrenergic fibers from pontine nuclei, especially the locus ceruleus
(Sawchenko & Swanson, 1982).
Both the alpha-1 adrenoceptor antagonist, prazosin, and the alpha-2
adrenoceptor agonist, clonidine, depressed copulation in male rats (J. T.
Clark, Smith, & Davidson, 1985). The alpha-2 antagonist yohimbine in-
creased sexual motivation and performance (J. T. Clark, Smith, & Davidson,
1984). Yohimbine also restored sexual activity in sexually exhausted male
rats (Rodriguez-Manzo & Fernandez-Guasti, 1994). Clonidine delivered
intracerebroventricularly or into the MPOA suppressed copulatory behavior
(J. T. Clark, 1991). Lesion of the locus ceruleus or administration of nor-
adrenaline synthesis inhibitors inhibited sexual function by increasing the
postejaculatory refractory period and the mount and intromission latencies
(Mclntosh & Barfield, 1984). An alpha-1 agonist was also shown to facilitate
ejaculation (J. T. Clark, Kalra, & Kalra, 1987). Intrathecal noradrenaline
accelerated pelvic thrusting (Hernandez-Gonzalez, Oropeza, Guevara, Cer-
vantes, & Morali, 1994). The role of central noradrenaline in female sexual
function is less understood. Noradrenergic nuclei in the brainstem are acti-
vated by copulatory behavior in female rats (Yang & Voogt, 2001). However,
lesions of the noradrenergic innervation of the hypothalamus did not affect
receptive behavior in female rats (Davis, Manzanares, Lookingland, Moore,

& Clemens, 1991). No studies have been reported on the effects of central
noradrenergic pathways on female sexual genital arousal or climax.
The effects of noradrenergic agents in male animals have led to studies
assessing their potential use in the treatment of erectile dysfunction in men.
Phentolamine, an alpha-1 receptor antagonist, has been evaluated for its
use in treating erectile dysfunction. It was found to be moderately effective
(I. Goldstein, 2000; I. Goldstein, Carson, Rosen, &. Islam, 2001; Gwinup,
1988; Zorgniotti, 1992, 1994; Zorgnotti & Lizza, 1994). A direct comparison
with sildenafil (Viagra) or one of the newer phosphodiesterase Type 5
inhibitors will be necessary to determine it relative efficacy and side-effect
profile. Yohimbine is an alkaloid extracted from an African bark. It is an
alpha-2 antagonist that has been used for over a century for sexual purposes
either as an herbal preparation or the pure compound (Morales, 2000). Its site
of action is probably in the central nervous system, because intracavernous
injection of alpha-2 antagonists does not produce erection (Brindley, 1986a).
Trials with patients who experience organic impotence showed only mar-
ginal effects (Morales, Condra, & Owen, 1987). Slightly better results were
seen with patients who experience psychogenic impotence (Morales et al.,
1987; Reid et al., 1987). A meta-analysis of yohimbine trials demonstrated
that yohimbine was superior to placebo in the treatment of erectile dysfunc-
tion. However, the overall effect is not remarkable (Carey & Johnson, 1996;
Ernst & Pittler, 1998).
Oxytocin
Spinal autonomic nuclei are innervated by oxytocin containing neu-

rons in the PVN (Sawchenko & Swanson, 1982; Swanson & Kuypers,
1980; Wagner & Clemens, 1991). The PVN was consistently labeled after
pseudorabies virus injection into the penis and the penile muscles, ischiocav-
ernosus and bulbospongiosus (Marson & McKenna, 1996; Marson et al.,
1993; Tang et al., 1999). The lumbosacral projections to the lumbosacral
spinal cord neurons, identified as projecting to the pelvic organs, were found
to contain oxytocin (Tang et al., 1999). Oxytocin receptors were found in
the sacral parasympathetic nucleus and interneurons in the dorsal gray
commissure of the L6-S1 spinal cord (Veronneau-Longueville et al., 1999).
The PVN is activated during sexual arousal, and especially at orgasm, as
indicated by the fact that plasma oxytocin concentrations increased in
male and female humans (Carmichael et al., 1987; Murphy, Seckl, Burton,
Checkley, & Lightman, 1987).
Oxytocin activates penile erections when injected into the lateral
ventricles or directly into the PVN in rats (Argiolas, 1992; Argiolas, Melis,
&. Gressa, 1986; Melis, Succu, lannucci, & Argiolas, 1997a). The explana-
tion for the effect of oxytocin injected into the PVN is that oxytocin
KEVIN E. McKENNA
stimulates oxytocinergic receptors located on the cell bodies of oxytocinergic
neurons in the PVN (Argiolas, 1992; Argiolas et al., 1986). Thus, oxytocin
neurons are excitatory to themselves. An oxytocin innervation of oxytocin-
ergic neurons has been identified in the supraoptic and PVN nuclei
(Theodosis, 1985).
A spinal site of action of oxytocin has also been identified. Intrathecal
administration of oxytocin and a specific oxytocin agonist were found to
cause erection in a dose'dependent manner in anesthetized rats (Giuliano,
Bernabe, McKenna, Longueville, & Rampin, 2001). The erectile response
was blocked by a specific oxytocin antagonist and was not elicited by a
closely related peptide, vasopressin. These results indicate that oxytocin
may be proerectile at both hypothalamic and spinal sites. The effects of
oxytocin on ejaculation and female sexual function have not been evaluated.
However, there is a considerable literature on the role of oxytocin in pair
bonding (Carter, 1998).
Adrenocorticotropin and Related Peptides
Several biologically active peptides are derived from pro-opiomelano-

cortin, including adrenocorticotropic (ACTH) and the alpha-melanocyte-
stimulating hormones (alpha-MSH). Both ACTH and alpha-MSH have
been shown to give rise to erectile responses. A syndrome of penile erection
and ejaculation, grooming, stretching, and yawning is produced after injec-
tion into the brain or hypothalamus (Argiolas, Melis, Murgia, & Schioth,
2000; Bertolini, Gessa, & Ferrari, 1975; Ferrari, Gessa* & Vargiu, 1963;
Mains, Eippers, & Ling, 1977; Poggioli, Arletti, Benelli, Cavazzuti, & Bertol-
ini, 1998). A major site of action is in the PVN, dorsomedial nucleus,
ventromedial nucleus, and anterior hypothalamic area (Argiolas et al., 2000).
However, there also appears to be a spinal, and possibly peripheral, site of
action. A synthetic melanocortin peptide, Melanotan II, induced erection
in spinal transected rats (Wessels et al., 2003). The sexual effects of alpha-
MSH and ACTH are due to stimulation of the melanocortin (MC) receptors.
There are five different melanocortin receptor subtypes (Wikberg, 1999;
Wikberg et al., 2000). There are several major drug development programs
related to these receptors because melanocortin inhibits feeding, and drugs
stimulating these receptors may be useful in treating obesity. The proerectile
effect appears to be largely due to stimulation of MC4 receptors (Van der
Ploeg et al., 2002). It is interesting that these authors also reported MC4
receptors on sensory receptors in the glans of the penis. This suggests that
melanocortins may also modulate genital sensory stimulation. Melanotan
II has been administered subcutaneously to men with erectile dysfunction.
It induced potent erections (Wessels et al., 1998; Wessels, Levine, Hadley,
Dorr, & Hruby, 2000). A closely related compound, PT 141, is being tested

as a treatment for erectile dysfunction using intranasal delivery (peptides
are degraded when given orally).
Opiates
Chronic use of opiates is associated with severe sexual dysfunction,

suggesting a central regulation of sexual function by endogenous opiate
systems (Crowley & Simpson, 1978; Cushman, 1972). Administration of
opiates depresses copulatory behavior in rats injected systemically (Mcln-
tosh, Vallano, &. Barfield, 1980; Pfaus & Gorzalka, 1987) into the brain or
hypothalamus (Hughes, Everitt, & Herbert, 1987; Mclntosh et al., 1980;
Melis, Stancampiano, Gessa, & Argiolas, 1992; Melis, Succu, & Argiolas,
1997). The sexual inhibitory effects of opiates are believed to be due to the
stimulation of mu opiate receptor on oxytocinergic neurons in the PVN
(Melis, Succu, lannucci, & Argiolas, 1997b). In anesthetized animals, injec-
tion of the opiate antagonist naloxone induced erections (Domer, Wessler,
Brown, & Matthews, 1988) and potentiated the erectile response of apomor-
phine in unanesthetized animals (Berendsen & Gower, 1986). In normal
humans, naloxone was without effect on arousal (A. Goldstein & Hansteen,
1977). Another opiate antagonist that is orally active, naltrexone, was
administered to impotent men in two small trials. It caused a significant
improvement in erectile function (Fabbri et al., 1989; J. A. Goldstein, 1986).
Nitric Oxide
The role of nitric oxide in mediating the vasodilation during penile

erection is well known. Anatomical and pharmacological evidence indicate
that nitric oxide may be part of the central nervous system control of sexual
function. There is a high concentration of nitric oxide synthase (NOS),
the synthetic enzyme for nitric oxide, in the PVN (Bredt, Hwang, & Snyder,
1990). The PVN also contains a splice variant isoform of NOS that is
found primarily in the penis (Ferrini, Magee, Vernet, Rajfer, & Gonzalez-
Cadavid, 2003).
A crucial role for nitric oxide in the PVN has been identified. Inhibition
of nitric oxide in the PVN inhibits the proerectile effects of dopamine and
oxytocin (Argiolas, 1994). Nitric oxide donors injected into the PVN cause
erection (Melis & Argiolas, 1995). Levels of nitric oxide in the PVN increase
during erection and copulation (Melis, Succu, lannucci, & Argiolas, 1998).
Nitric oxide also plays a role in the MPOA. Nitric oxide levels there increase
during copulation, and nitric oxide inhibition decreased copulatory behavior
(Sato et al., 1999; Sato, Horita, Kurohata, Adachi, & Tsukamoto, 1998).
Anatomical studies have demonstrated localization of nitric oxide synthase
in neurons involved in the control of pelvic and autonomic function (Burnett
90 KEVIN E. McKENNA
et al., 1995; Dun et al., 1993; Saito et al., 1994; Valtschanoff, Weinberg,
& Rustioni, 1992). Intrathecal administration of nitric oxide inhibitor
blocked the proerectile effects of intrathecally delivered oxytocin, indicating
that the effects of oxytocin in the spinal cord are mediated through nitric
oxide interneurons. Volatile nitrites ("poppers") have been used extensively
in sexual contexts. These produce an intense, brief "rush" with pounding
heart, flushing, and mental dissociation. In sexual situations, users report
heightened sexual arousal and loss of inhibitions. It is commonly reported
that they relax smooth muscle of the anal sphincters, facilitating anal sex.
However, whether this is for central nervous system effects or peripheral
effects is unclear.
CONCLUSIONS
This chapter has demonstrated that there has been a tremendous

increase recently of our understanding of the neurophysiology, neuroanat-
omy, and pharmacology of the central nervous system control of sexual
function. The crucial role of the PVN and the nPGi has been identified.
The inhibitory role of serotonin and the excitatory role of oxytocin and
dopamine have been established. However, there exist many substantial
gaps in our knowledge. Most of the research has been on the central control
of penile erection. The central control and neurochemistry of ejaculation
and sexual motivation are far less well understood. And, most glaringly, the
central control of female sexual function is largely obscure. This is largely
a result of issues relating to animal models. Most research has been focused
on the neural and hormonal control of lordosis and female receptivity and
proceptivity. Animal models for female genital responses are not as well
developed as those for erection and ejaculation. Future research needs to
be directed at these crucial issues.
REFERENCES
Ackerman, A. E., Lange, G. M, & Clemens, L. G. (1997). Effects of paraventricular

lesions on sex behavior and seminal emission in male rats. Physiology and
Adler, N. T., Davis, P. G., &. Komisaruk, B. R. (1977). Variation in the size and
sensitivity of a genital sensory field in relation to the estrous cycle in rats.
Hormones and Behavior, 9, 334-344.
Ahlenius, S., Larsson, K., Svensson, L., Hjorth, S., Carlsson, A., &. Lindberg, P.
(1981). Effects of a new type of 5-HT receptor agonist on male rat sexual
behaviour. Pharmacology Biochemistry and Behavior, 15, 785.

Allard, J., Bernabe, J., Derdinger, F., Alexandra, L., McKenna, K., & Giuliano, F.
(2002). Selegiline enhances erectile activity induced by dopamine injection
in the paraventricular nucleus of the hypothalamus in anesthetized rats. Inter-
national Journal of Impotence Research, 14, 518-522.
Aloi, J. A., Insel, T. R., Mueller, E. A., & Murphy, D. L. (1984). Neuroendocrine
and behavioral effects of m-chlorophenylpiperazine administration in rhesus
monkeys. Life Science, 34, 1325-1331.
Andersson, K.-E., & Wagner, G. (1995). The physiology of penile erection. Physio-
logical Reviews, 75, 191-236.
Argiolas, A. (1992). Oxytocin stimulation of penile erection: Pharmacology, site,
and mechanism of action. Annals of the New York Academy of Sciences, 652,
194-203.
Argiolas, A. (1994). Nitric oxide is a central mediator of penile erection. Neurophar-
macology, 33, 1339-1344.
Argiolas, A., Melis, M. R., &. Gessa, G. L. (1986). Oxytocin: An extremely potent
inducer of penile erection and yawning in male rats. European Journal of
Argiolas, A., Melis, M. R., Murgia, S., &. Schioth, H. B. (2000). ACTH- and alpha-
MSH induced grooming, stretching, yawning and penile erection in male rats:
Site of action in the brain and role of melanocortin receptors. Brain Research
Bulletin, 51, 425-431.
Argiolas, A., Melis, M. R., Vargiu, L., & Gessa, G. L. (1987). d(CH2) 5Tyr (Me)-
Orn8-vasotocin, a potent oxytocin antagonist, antagonizes penile erection and
yawning induced by oxytocin and apomorphine, but not by ACTH (1-24).
European Journal of Pharmacology, 134, 221-224.
Azadzoi, K. M., Payton, T., Krane, R. J., &. Goldstein, I. (1990). Effects of intracaver-
nosal trazodone hydrochloride: Animal and human studies. Journal of Urology,
144, 1277-1282.
Bancila, M., Verge, D., Rampin, O., Backstrom, J. R., Sanders-Bush, E., McKenna,
K. E., et al. (1999). 5-Hydroxytryptamine 2C receptors on spinal neurons
controlling penile erection in the rat. Neuroscience, 92, 1523-1537.
Bandler, R., & Shipley, M. T. (1994). Columnar organization in the midbrain
periaqueductal gray: Modules for emotional expression? Trends in Neurosciences,
17, 379-389.
Barfield, R. J., Wilson, C., & McDonald, P. G. (1975). Sexual behavior: Extreme
reduction of postejaculatory refractory period by midbrain lesions in male rats.
Science, 189, 147-149.
Barnes, N. M., & Sharp, T. (1999). A review of central serotonin receptors and
their function. Neuropharmacology, 38, 1083-1152.
Barrington, F. J. F. (1925). The effects of lesions of the hind- and mid-brain on
micturition in the cat. Quarterly Journal of Experimental Physiology, 15, 81-102.
Baum, M. J., &. Everitt, B. J. (1992). Increased expression of c-fos in the medial
preoptic area after mating in male rats: Role of afferent inputs from the medial
amygdala and midbrain central tegmentalfield. Neuroscience, 50, 627-646.
92 KEVIN E. McKENNA
Bazzett, T. J., Eaton, R. C., Thompson, J. T., Markowski, V. P., Lumley, L A., &
Hull, E. M. (1991). Dose dependent D2 effects on genital reflexes after MPOA
injections of quinelorane and apomorphine. Life Science, 48, 2309-2315.
Beach, F. A. (1967). Cerebral and hormonal control of reflexive mechanisms in-
volved in copulatory behavior. Physiological Reviews, 47, 289-316.
Behbehani, M. M. (1995). Functional characteristics of the midbrain periaqueductal
gray. Progress in Neurobiology, 46, 574-605.
Bell, C. (1972). Autonomic nervous control of reproduction: Circulatory and other
factors. Pharmacological Reviews, 24, 657-736.
Berendsen, H. H., & Broekkamp, C. L. (1987). Drug-induced penile erections in
rats: Indications of serotonin IB receptor mediation. European Journal of Phar-
macology, 135, 279-287.
Berendsen, H. H., Broekkamp, C. L., & van Delft, A. M. (1991). Depletion of brain
serotonin differently affects behaviors induced by 5HT1 A, 5HT1C, and 5HT2
receptor activation in rats. Behavior Neural Biology, 55, 214-226.
Berendsen, H. H., & Gower, A. J. (1986). Opiate-androgen interactions in drug-
induced yawning and penile erections in the rat. Neuroendocrinolog}, 42, 185-
190.
Berendsen, H. H., Jenck, F., & Broekkamp, C. L. (1990). Involvement of serotonin
1C receptors in drug-induced penile erections in rats. Psychopharmacology (Ber-
lin), 101, 57-561.
Berkley, K. J., Robbins, A., & Sato, Y. (1987). Uterine afferent fibers in the rat.
In R. F. Schmidt, H.-G. Schaible, & C. Vahle-Hinz (Eds.), Fine afferent nerve
fibers and pain (pp. 129-136). Weinheim, Germany: VCH Verlag.
Bernabe, J., Rampin, O., Giuliano, F., &. Benoit, G. (1995). Intracavernous pressure
changes during reflexive penile erections in the rat. Physiology and Behavior,
57, 837-841.
Bertolini, A., Gessa, G. L., & Ferrari, W. (1975). Penile erection and ejaculation:
A central effect of ACTH-like peptides in mammals. In M. Sandier & G. L.
Gessa (Eds.), Sexual behavior: Pharmacology and biochemistry (pp. 247-257).
New York: Raven Press.
Birder, L. A., Roppolo, J. R., ladarola, M. J., & de Groat, W. C. (1991). Electrical
stimulation of visceral afferent pathways in the pelvic nerve increases c-fos in
the rat lumbosacral spinal cord. Neuroscience Letters, 129, 193-196.
Bitran, D., & Hull, E. M. (1987). Pharmacological analysis of male rat sexual
behavior. Neuroscience and Biobehavioral Review, 11, 365-389.
Bjorklund, A., Lindvall, O., & Nobin, A. (1975). Evidence of an incertohypotha-
lamic dopamine neuron system in the rat. Brain Research, 89, 29-42.
Bors, E., & Blinn, K. A. (1959). Bulbocavernosus reflex. Journal of Urology, 82, 128-
130.
Bors, E., & Comarr, A. E. (1960). Neurological disturbances of sexual function
with special reference to 529 patients with spinal cord injury. Urologicai Survey,
10, 191-222.

Brackett, N. L, & Edwards, D. A. (1984). Medial preoptic connections with the
midbrain tegmentum are essential for male sexual behavior. Physiology and
Brackett, N. L., luvone, P. M., & Edwards, D. A. (1986). Midbrain lesions, dopa-
mine and male sexual behavior. Behavioral Brain Research, 20, 231-240.
Bredt, D. S., Hwang, P. M., & Snyder, S. H. (1990). Localization of nitric oxide
synthase indicating a neural role for nitric oxide. Nature (London), 347, 768-
770.
Breedlove, S. M., & Arnold, A. P. (1981). Sexually dimorphic motor nucleus in
the rat lumbar spinal cord: Response to adult hormone manipulation, absence
in androgen insensitive rats. Brain Research, 225, 297-307.
Brindley, G. S. (1986a). Pilot experiments on the actions of drugs injected into the
human corpus cavernosum penis. British Journal of Pharmacology, 87, 495-500.
Brindley, G. S. (1986b). Sexual and reproductive problems of paraplegic men. In
J. R. Clarke (Ed.), Oxford reviews of reproductive biology (pp. 214-222). Oxford,
England: Clarendon Press.
Buijs, R. M. (1978). Infra- and extrahypothalamic vasopressin and oxytocin path-
ways in the rat: Pathways to the limbic system, medulla oblongata and spinal
cord. Cell and Tissue Research, 192, 423-435.
Burnett, A. L., Lowenstein, C. J., Bredt, D. S., Chang, T. S. H., & Snyder, S. H.
(1992). Nitric oxide: A physiologic mediator of penile erection. Science,
257, 401-403.
Burnett, A. L., Saito, S., Maguire, M. P., Yamaguchi, H., Chang, T. S., & Hanley,
D. F. (1995). Localization of nitric oxide synthase in spinal nuclei innervating
pelvic ganglia. Journal of Urology, 153, 212-217.
Card, J. P., Rinaman, L., Lynn, R. B., Lee, B.-H., Meade, R. P., Miselis, R. R., &
Enquist, L. W. (1993). Pseudorabies virus infection of the rat central nervous
system: Ultrastructural characterization of viral replication, transport, and
pathogenesis. Journal ofNeuroscience, 13, 2515-2539.
Carey, M. P., & Johnson, B. T. (1996). Effectiveness of yohimbine in the treatment
of erectile disorder: Four meta-analytic integrations. Archives of Sexual Behavior,
25, 341-360.
Carlson, R. R., & De Feo, V. J. (1965). Role of the pelvic nerve vs. the abdominal
sympathetic nerves in the reproductive function of the female rat. Endocrinol-
ogy, 77, 1014-1022.
Carmichael, M. S., Humbert, R., Dixon, J., Palmisano, G., Greenleaf, W., & David-
Carro-Juarez, M., & Rodriguez-Manzo, G. (2001). Exhaustion of the coital reflex in
spinal male rats is reversed by the serotonergic agonist 8-OH-DPAT. Behavioral
Carter, C. S. (1998). Neuroendocrine perspectives on social attachment and love.
Psychoneuroendocrinology, 23, 779-818.
94 KEVIN E. McKENNA
Cechetto, D. F., &. Saper, C. B. (1988). Neurochemical organization of the hypo-
thalamic projection to the spinal cord in the rat. Journal of Comparative Neuroi-
ogy, 272, 579-604.
Chambers, K. C., & Phoenix, C. H. (1989). Apomorphine, deprenyl, and yohimbine
fail to increase sexual behavior in rhesus males. Behavioral Neuroscience,
103, 816-823.
Chen, K. K., Chan, S. H. H., Chang, L. S., & Chan, J. Y. H. (1997). Participation
of paraventricular nucleus of hypothalamus in central regulation of penile
erection in the rat. Journal of Urology, 158, 238-244.
Clark, J. T. (1991). Suppression of copulatory behavior in male rats following
central administration of clonidine. Neuropharmacolagy, 130, 373-382.
Clark, J.T., Kalra, S. P., & Kalra, P. S. (1987). Effects of a selective alpha 1-
adrenoceptor agonist, methoxamine, on sexual behavior and penile reflexes.
Physiology and Behavior, 140, 747-753.
Clark, J. T., Smith, E. R., &. Davidson, J. M. (1984)- Enhancement of sexual motiva-
tion in male rats by yohimbine. Science, 1225, 847-849.
Clark, J. T., Smith, E. R., & Davidson, J. M. (1985). Evidence for the modulation
of sexual behavior by alpha-adrenoceptors in male rats. Neuroendocrinology,
41,36-43.
Clark, T. K., Caggiula, A. R., McConnel, R. A., & Antelman, S. M. (1975). Sexual
inhibition is reduced by rostral midbrain lesions in the male rat. Science,
190, 169-171.
Coolen, L. M., Peters, H. J. P. W., &. Veening, J. G. (1996). Fos immunoreactivity
in the rat brain following consummatory elements of sexual behavior: A sex
comparison. Brain Research, 738, 67-82.
Courty, E., Durif, F., Zenut, M., Courty, P., & Lavarenne, J. (1997). Psychiatric
and sexual disorders induced by apomorphine in Parkinson's disease. CJinicai
Neuropharmacology 20, 140-147.
Crowley, T. J., & Simpson, A. (1978). Methadone dose and human sexual behavior.
International Journal of Addiction, 31, 285-295.
Cushman, P. (1972). Sexual behavior in heroin addiction and methadone mainte-
nance. Correlation with plasma luteinizing hormone. New York State Journal
of Medicine, 72, 1261-1265.
Davidson, J. M. (1966). Activation of male rat's sexual behavior by intracerebral
implantation of androgen. Endocrinology, 79, 783-794-
Davis, B. L., Manzanares, J., Lookingland, K. J., Moore, K. E., & Clemens, L. G.
(1991). Noradrenergic innervation to the VMN or MPN is not necessary for
lordosis. Pharmacology Biochemistry and Behavior, 39, 737-742.
De Groat, W. C., & Booth, A. M. (1993). Neural control of penile erection. In
C. A. Maggi (Ed.), The autonomic nervous system: Nervous control of the urogenital
system (pp. 465-513). London: Harwood.
De Groat, W. C., & Steers, W. D. (1990). Autonomic regulation of the urinary
bladder and sexual organs. In A. D. Loewy & K. M. Spyer (Eds.), Central

regulation of autonomic functions (pp. 310-333). New York: Oxford Univer-
sity Press.
Domer, F. R., Wessler, G., Brown, R. L, & Matthews, A. (1988). Effects of naloxone
on penile erection in cats. Pharmacology Biochemistry and Behavior, 30, 543-545.
Du, H.-J. (1989). Medullary neurons with projections to lamina X of the rat
as demonstrated by retrograde labeling after HRP microelectrophoresis Brain
Research, 505, 135-140.
Dun, N. J., Dun, S. L., Wu, S. Y., Forstermann, U., Schmidt, H. H., &. Tseng, L. F.
(1993). Nitric oxide synthase immunoreactivity in the rat, mouse, cat and
squirrel monkey spinal cord. Neuroscience, 54, 845-857.
Erlandson, B. E., Fall, M., &. Carlsson, C. A. (1977). The effect of intravaginal
electrical stimulation on the feline urethra and urinary bladder: Electrical
parameters. Scandinavian Journal of Urology Nephrology Supplement, 44, 5-18.
Ernst, E., & Pittler, M. H. (1998). Yohimbine for erectile dysfunction: A systematic
review and meta-analysis of randomized clinical trials. Journal of Urology,
159, 433-436.
Erskine, M. S. (1993). Mating-induced increases in FOS protein in preoptic area and
medial amygdala of cycling female rats. Brain Research Bulletin, 32, 447-451.
Everitt, B. J., Cador, M., & Robbins, T. W. (1989). Interactions between the
amygdala and ventral striatum in stimulus-reward associations: Studies using
a second-order schedule of sexual reinforcement. Neuroscience, 30, 63-75.
Everitt, B. J., Fuxe, K., Hokfelt, F. T., & Jonsson, C. (1975). Role of monoamines
in the control by hormones of sexual receptivity in the female rat. Journal of
Comparative Physiology and Psychology, 89, 556-572.
Everitt, B. J., & Stacey, P. (1987). Studies of instrumental behavior with sexual
reinforcement in male rats: II: Effects of preoptic lesions, castration and testos-
terone. Journal of Comparative Psychology, 101, 407-419.
Fabbri, A., Jannini, E. A., Gnessi, L., Moretti, C., Ulisse, S., Franzese, A., et al.
(1989). Endorphins in male impotence: Evidence for naltrexone stimulation
of erectile activity in patient therapy. Ps;ychoneuroendocrinoiog}i, 14, 103-111.
Fedirchuk, B., Song, L., Downie, J. W., & Shefchyk, S. J. (1992). Spinal distribution
of extracellular field potentials generated by electrical stimulation of pudendal
and perineal afferents in the cat. Experimental Brain Research, 89, 517-520.
Femandez-Guasti, A., Escalante, A. L., Ahlenius, S., Hillegaart V., & Larsson, K.
(1992). Stimulation of 5-HT1A and 5-HT1B receptors in brain regions and
its effects on male rat sexual behavior. European Journal of Pharmacology,
210, 121-129.
Ferrari, W., Gessa, G. L., &. Vargiu, L. (1963). Behavioural effects induced by
intracisternally injected ACTH and MSH. Annals of the New York Academy
of Sciences, 104, 330-345.
Ferrini, M. G., Magee, T. R., Vernet, D., Rajfer, ]., & Gonzalez-Cadavid, N. F.
(2003). Penile neuronal nitric oxide synthase and its regulatory proteins are
96 KEVIN E. McKENNA
present in hypothalamic and spinal cord regions involved in the control of
penile erection. Journal of Comparative Neurology, 458, 46-61.
Foreman, M. M., Fuller, R. W., Rasmussen, K., Nelson, D. L., Calligaro, D. O.,
Zhang, L., et al. (1994). Pharmacological characterization of LY293284: A
5-HT1A receptor agonist with high potency and selectivity. Journal of Pharma-
cology Experimental Therapeutics, 270, 1270-1281.
Foreman, M. M., & Hall, J. L. (1987). Effects of D2 dopaminergic receptor stimula-
tion on the lordotic response of female rats. Psychopharmacology (Berlin), 91,
96-100.
Fukuda, H., &. Fukai, K (1986a). Ascending and descending pathways of reflex
straining in the dog. Japanese Journal of Physiology, 36, 905-920.
Fukuda, H., & Fukai, K. (1986b). Location of the reflex centre for straining elicited
by activation of pelvic afferent fibres of decerebrate dogs. Brain Research,
380, 287-296.
Fukuda, H., & Fukai, K. (1988). Discharges of bulbar respiratory neurons during
rhythmic straining evoked by activation of pelvic afferent fibers in dogs. Brain
Research, 449, 157-166.
Fukuda, H., Fukai, K., Yamane, M., &. Okada, H. (1981). Pontine reticular unit
responses to pelvic nerve and colonic mechanical stimulation in the dog. Brain
Research, 207, 59-71.
Gerhardt, C. C., & van Heerikhuizen, H. (1997). Functional characteristics of
heterologously expressed serotonin receptors. European Journal of Pharmacology,
334, 1-23.
Giuliano, F., Allard, J., Rampin, O., Droupy, S., Benoit, G., Alexandre, L., &
Bernabe, J. (2002). Pro-erectile effect of systemic apomorphine: Existence of
a spinal site of action. Journal of Urology, 167, 402-406.
Giuliano, F., Bernabe, J., McKenna, K., Longueville, F., & Rampin, O. (2001).
Spinal proerectile effect of oxytocin in anesthetized rats. American Journal of
Physiology, 280, R1870-R1877.
Giuliano, F., Rampin, O., Brown, K., Courtois, F., Benoit, G., &L Jardin, A. (1996).
Stimulation of the medial preoptic area of the hypothalamus in the rat elicits
increases in intracavernous pressure. Neuroscience Letters, 209, 1-4.
Goldstein, A., & Hansteen, R. W. (1977). Evidence against involvement of en-
dorphine in sexual arousal and orgasm in man. Archives of General Psychiatry,
34, 1179-1180.
Goldstein, I. (2000). Oral phentolamine: An alpha-1, alpha-2 adrenergic antagonist
for the treatment of erectile dysfunction. Internationa/ Journal of Impotence
Research, I2(Suppl. 1), S75-S80.
Goldstein, L, Carson, C., Rosen, R., & Islam, A. (2001). Vasomax for the treatment
of male erectile dysfunction. World Journal of Urology, 19, 51-56.
Goldstein, J. A. (1986). Erectile function and naltrexone. Annals of Internal Medi-
cine, 105, 99.

Goodwin, F. K. (1971). Psychiatric side effects of levodopa in man. Journal of the
American Medical Association, 218, 1915-1920.
Greco, B., Edwards, D. A., Michael, R. P., & Clancy, A. N. (1996). Androgen
receptor immunoreactivity and mating-induced Fos expression in forebrain
and midbrain structures in the male rat. Neuroscience, 75, 161-171.
Gwinup, G. (1988). Oral phentolamine in non-specific erectile insufficiency. Annals
of Internal Medicine, 109, 162-163.
Hamburger-Bar, R., & Rigter, H. (1975). Apomorphine: Facilitation of sexual
behaviour in female rats. European Journal of Pharmacology, 32, 357-360.
Hancock, M. B., &. Peveto, C. A. (1979a). A preganglionic autonomic nucleus in
the dorsal gray commissure of the lumbar spinal cord of the rat. Journal of
Hancock, M. B., & Peveto, C. A. (1979b). Preganglionic neurons in the sacral
spinal cord of the rat: An HRP study. Neuroscience Letters, 11, 1-5.
Hart, B. L., & Leedy, M. G. (1985). Neurological bases of male sexual behaviour:
A comparative analysis. In N. Adler, D. Pfaff, & R. W. Goy (Eds.), Handbook
of behavioral neurobiology: Vol. 7. Reproduction (pp. 373-422). New York: Ple-
num Press.
Hasson, H. M. (1993). Cervical removal at hysterectomy for benign disease: Risks
and benefits. Journal of Reproductive Medicine, 38, 781-790.
Hayes, E. S., Doherty, P. C., Hanson, L. A., Gorzalka, B. B., & Adaikan, P. G.
(2000). Proerectile effects of novel serotonin agonists. International Journal of
Impotence Research, 12(Suppl. 3), S62.
Heaton, J. P. (2001). Apomorphine: An update of clinical trial results. International
Journal of Impotence Research, 12(Suppl. 4), S67-S73.
Hernandez-Gonzalez, M., Oropeza, M. V., Guevara, M. A., Cervantes, M., & Mor-
ali, G. (1994). Effects of intrathecal administration of adrenergic agonists on
the frequency of copulatory pelvic thrusting of the male rat. Archives of Medical
Research, 25, 419-425.
Holstege, G., Griffiths, D., De Wall, H., & Dalm, E. (1986). Anatomical and
physiological observations on supraspinal control of bladder and urethral
sphincter muscles in the cat. Journal of Comparative Neurology, 250, 449-461.
Holstege, G., Kuypers, H. G. J. M., & Boer, R. C. (1969). Anatomical evidence
for direct brain stem projections to the somatic motoneuronal cell groups
and autonomic preganglionic cell groups in cat spinal cord. Brain Research,
171,329-333.
Holstege, J. C. (1987). Brainstem projections to lumbar motoneurons in rat: II. An
ultrastructural study by means of the anterograde transport of wheat germ
agglutinin coupled to horseradish peroxidase and using the tetramethyl benzi-
dine reaction. Neuroscience, 21, 369-376.
Honda, C. N. (1985). Visceral and somatic afferent convergence onto neurons near
the central canal in the sacral spinal cord of the cat. Journal ofNeurophysiology,
I I , 1059-1076.
98 KEVIN E. McKENNA
Hubscher, C. H., & Johnson, R. D. (1996). Responses of medullary reticular forma-
tion neurons to input from the male genitalia. Journal of Neurophysiology,
76, 2474-2482.
Hughes, A.M., Everitt B.J., & Herbert, J. (1987). Selective effects of beta-
endorphin infused into the hypothalamus, preoptic area and bed nucleus of
the stria terminalis on the sexual and ingestive behavior of male rats. Neurosci-
ence, 23, 1063-1073.
Hull, E. M. (1995). Dopaminergic influences on male rat sexual behavior. In
P. Micevych & R. P. Hammer (Eds.), Neurobiological effects of sex steroid hor-
mones (pp. 234-253). Cambridge, England: Cambridge University Press.
Hull, E. M., Bitran, D., Pehek, E. A., Warner, R. K., Band, L. C., & Holmes, G. M.
(1986). Dopaminergic control of male sex behavior in rats: Effects of an
intracerebrally-infused agonist. Brain Research, 370, 73-81.
Hull, E. M., Du, J., Lorrain, D. S., & Matuszewich, L. (1995). Extracellular dopamine
in the medial preoptic area: Implications for sexual motivation and hormonal
control of copulation. Journal of Neuroscience, 15, 7465-7471.
Hull, E. M., Eaton, R. C., Markowski, V. P., Moses, J., Lumley, L. A., & Loucks,
J. A. (1992). Opposite influence of medial preoptic Dl and D2 receptors on
genital reflexes: Implications for copulation. Life Science, 51, 1705-1713.
Janig, W., & McLachlan, E. M. (1987). Organization of lumbar spinal outflow to
distal colon and pelvic organs. Physiological Reviews, 67, 1332-1403.
Jordan, C. L., Breedlove, S. M., & Arnold, A. P. (1982). Sexual dimorphism and
the influence of neonatal androgen in the dorsolateral motor nucleus of the
rat lumbar spinal cord. Brain Research, 249, 309-314.
Julien, E., &. Over, R. (1984). Male sexual arousal with repeated exposure to erotic
stimuli. Archives of Sexual Behavior, 13, 211-221.
Kluver, H., & Bucy, P. C. (1939). Preliminary analysis of the functions of the
temporal lobes in monkeys. Archives of Neurology and Psychiatry, 42, 979-1000.
Kojima, M., Matsuura, T., Tanaka, A., Amagai, T., Imanishi, J., & Sano, Y. (1985).
Characteristic distribution of noradrenergic terminals on the anterior horn
motoneurons innervating the perineal striated muscles in the rat. Anatomy
and Embryology, 171, 267-273.
Kollar, E. J. (1953). Reproduction in the female rat after pelvic neurectomy. Anatom-
ical Record, 115, 641-658.
Komisaruk, B. R., Adler, N. T., & Hutchinson, J. (1972). Genital sensory field:
enlargement by estrogen treatment in female rats. Science, 178, 1295-1298.
Komisaruk, B. R., Gerdes, C. A., & Whipple, B. (1997). "Complete" spinal cord
injury does not block perceptual responses to genital self-stimulation in women.
Kondo, Y., Yamanouchi, K., & Arai, Y. (1993). p-Chlorophenylalanine facilitates
copulatory behavior in septal lesioned but not in preoptic lesioned male rats.
Journal of Neuroendocrinology, 5, 629-633.

Kow, L.-M., & Pfaff, D. W. (1973). Effects of estrogen treatment on the size of
receptive field and response threshold of pudendal nerve in the female rat.
Neuroendocrinology, 13, 299-313.
Kuru, M. (1965). Nervous control of micturition Physiology Review, 45, 425.
Kuypers, H. G. J. M., & Ugolini, G. (1990). Viruses as transneuronal tracers. Trends
inNeurosciences, 13, 71-75.
Lai, S., Ackman, D., Thavundayil, J. X., Kiely, M. E., & Etienne, P. (1984). Effect
of apomorphine, a dopamine receptor agonist, on penile tumescence in normal
subjects. Progress in Neuropsychopharrwcology and Biological Psychiatry, 8, 695-
699.
Lai, S., Laryea, E., Thavundayil, J. X., Nair, N. P., Negrete, J., Ackman, D., et
al. (1987). Apomorphine-induced penile tumescence in impotent patients:
Preliminary findings. Progress in Neuropsychopharmacology and Biological Psy-
chiatry, 11, 235-242.
Lane, R. M. (1997). A critical review of selective serotonin reuptake inhibitor-
related sexual dysfunction; incidence, possible aetiology and implications for
management. Journal of Psychopharmacology, 11, 72-82.
Langworthy, O. R. (1965). Innervation of the pelvic organs of the rat. Investigative
Urology, 2, 491-511.
Lee, J.W., &. Erskine, M.S. (1996). Vaginocervical stimulation suppresses the
expression of c-fos induced by mating in thoracic, lumbar and sacral segments
of the female rat. Neuroscience, 74, 237-249.
Lindstrom, S., Fall, M., Carlsson, C. A., & Erlandson, B. E. (1983). The neurophysi-
ological basis of bladder inhibition in response to intravaginal electrical stimu-
lation. 'Journal of Urology, 29, 405-410.
Lindvall, O., Bjorklund, A., & Skagerberg, G. (1984). Selective histochemical
demonstration of dopamine terminal systems in rat di- and telencephalon:
New evidence for dopaminergic innervation of hypothalamic neurosecretory
nuclei. Brain Research, 306, 19-30.
Loewy, A. D., & McKellar, S. (1981). Serotonergic projections from the ventral
medulla to the intermediolateral cell column in the rat. Brain Research,
211, 146-152.
Loewy, A. D., McKellar, S., &. Saper, C. B. (1979). Direct projections from the
A5 catecholamine cell group to the intermediolateral cell column. Brain Re-
search, 174, 309-314.
Mains, R. E., Eippers, B. A., &Ling,N. (1977). Common precursor to the corticotro-
pins and endorphins. Proceedings of the National Academy of Sciences USA,
74, 3014-3018.
Malsbury, C. W. (1971). Facilitation of male rat copulatory behavior by electrical
stimulation of the medial preoptic area. Physiology and Behavior, 7, 797-805.
Marlier, L., Teilhac, J. R., Cerruti, C., & Privat, A. (1991). Autoradiographic
mapping of serotonin 1, serotonin 1A, serotonin IB and serotonin 2 receptors
in the rat spinal cord. Brain Research, 550, 15-23.
100 KEVIN E. McKENNA

Marson, L. (1995). Central nervous system neurons identified after injection of
pseudorabies virus into the rat clitoris Neuroscience Letters, 190, 41-44.
Marson, L., List, M. S., & McKenna, K. E. (1992). Lesions of the nucleus paragi-
gantocellularis alter ex copula penile reflexes. Brain Research, 592, 187-192.
Marson, L., & McKenna, K. E. (1990). The identification of a brainstem site
controlling spinal sexual reflexes in male rats. Brain Research, 515, 303-308.
Marson, L., &. McKenna, K. E. (1992). A role for 5-hydroxytryptamine in descend-
ing inhibition of spinal sexual reflexes. Experimental Brain Research, 88, 313-
320.
Marson, L., & McKenna, K. E. (1994). Stimulation of the hypothalamus initiates
the urethrogenital reflex in male rats. Brain Research, 638, 103-108.
Marson, L., & McKenna, K. E. (1996). CNS cell groups involved in the control
of the ischiocavernosus and bulbospongiosus muscles: A transneuronal tracing
study using pseudorabies virus. Journal of Comparative Neurology, 374, 161-179.
Marson, L., Platt, K. B., & McKenna, K. E. (1993). CNS innervation of the penis
as revealed by the transneuronal transport of pseudorabies virus. Neuroscience,
55, 263-280.
Martin, G. F., Vertes, R. P., & Waltzer, R. (1985). Spinal projections of the giganto-
cellular reticular formation in the rat: Evidence for projections from different
areas to laminae I and II and lamina IX. Experimental Brain Research, 58, 154-
162.
Matuszewich, L., Lorrain, D. S., & Hull, E. M. (2000). Dopamine release in the
medial preoptic area of female rats in response to hormonal manipulation and
sexual activity. Be/uiviorai Neuroscience, 114, 772-782.
Matuszewich, L., Lorrain, D. S., Trujillo, R., Dominguez, J., Putnam, S. K., & Hull,
E. M. (1999). Partial antagonism of 8-OH-DPAT's effects on male rat sexual
behavior with a D2, but not a 5-HT1 A, antagonist. Brain Research, 820, 55-62.
Mclntosh, T. K., & Barfield, R. J. (1984). Brain monoaminergic control of male
reproductive behavior: I. Serotonin and the postejaculatory period. Behavioral
Mclntosh, T. K., Vallano, M. L., & Barfield, R. J. (1980). Effects of morphine, beta-
endorphin and naloxone on catecholamine levels and sexual behavior in the
male rat. Pharmacology Biochemistry and Behavior, 13, 435-441.
McKenna, K. E., Chung, S. K., & McVary, K. T. (1991). A model for the study of
sexual function in anesthetized male and female rats. American Journal of
Physiology, 261, R1276-R1285.
McKenna, K. E., & Nadelhaft, I. (1986). The organization of the pudendal nerve
in the male and female rat. Journal of Comparative Neurology, 248, 532-549.
McKenna, K. E., & Nadelhaft, I. (1989). The pudendo-pudendal reflex in male
and female rats. Journal of Autonomic Nervous System, 27, 67-77.
Meisel, R. L., & Sachs, B. D. (1994). The physiology of male sexual behavior. In
E. Knobil & J. D. Neill (Eds.), The physiology of reproduction (pp. 3-105). New
York: Raven Press.

Melis, M. R., & Argiolas, A. (1995). Nitric oxide donors induce penile erection
and yawning when injected in the central nervous system of male rats. European
journal of Pharmacology, 294, 1-9.
Melis, M. R., Argiolas, A., &. Gessa, G. L. (1987). Apomorphine-induced penile
erection and yawning: Site of action in the brain. Brain Research, 415, 98-104.
Melis, M. R., Argiolas, A., & Gessa, G. L. (1989). Evidence that apomorphine
induces penile erection and yawning by releasing oxytocin in the central
nervous system. European journal of Pharmacology, 164, 565-570.
Melis, M. R., Stancampiano, R., Gessa, G. L., &. Argiolas, A. (1992). Prevention
by morphine of apomorphine- and oxytocin-induced penile erection: Site of
action in the brain. Neuropsychopharmacology, 6, 17-21.
Metis, M. R., Succu, S., &. Argiolas, A. (1997). Prevention by morphine of
N-methyl'D'aspartic acid-induced penile erection and yawning: Involvement
of nitric oxide. Brain Research Bulletin, 44, 689-694-
Melis, M. R., Succu, S., lannucci, U., & Argiolas, A. (1997a). Oxytocin increases
nitric oxide production in the paraventricular nucleus of the hypothalamus of
male rats: Correlation with penile erection and yawning. Regulator); Peptides,
69, 105-111.
Melis, M. R., Succu, S., lannucci, U., & Argiolas, A. (1997b). Prevention by
morphine of apomorphine- and oxytocin-induced penile erection and yawning:
Involvement of nitric oxide. Naunyn Schmiedebergs Archives of Pharmacology,
355, 595-600.
Melis, M. R., Succu, S., lannucci, U., & Argiolas, A. (1998). Nitric oxide production
is increased in the paraventricular nucleus of the hypothalamus of male rats
during non-contact penile erections and copulation. European journal of Neuro-
science, 10, 1968-1974.
Merari, A., &. Ginton, A. (1975). Characteristics of exaggerated sexual behavior
induced by electrical stimulation of the medial preoptic area in male rats.
Millan, M. J., Peglion, J. L., Lavielle, G., & Perrin-Monneyron, S. (1997). Serotonin
2C receptors mediate penile erections in rats: Actions of novel and selective
agonists and antagonists. European journal of Pharmacology, 325, 9-12.
Miller, N. S., & Gold, M. S. (1988). The human sexual response and alcohol and
drugs, journal Substance Abuse Treatment, 5, 171-177.
Modell, J. G., Katholi, C. R., Modell, J. D., & DePalma, R. L. (1997). Comparative
sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline. Clinical
Pharmacology and Therapeutics, 61, 476-487.
Monsma, F. J., Shen, Y., & Ward, R. P. (1993). Cloning and expression of a novel
serotonin receptor with high affinity for tricyclic psychotropic drugs. Molecular
Morales, A. (2000). Yohimbine in erectile dysfunction: The facts. International
journal of Impotence Research, 12(Suppl. 1), S70-S74.

Morales, A., Condra, M, & Owen, J. A. (1987). Is yohimbine effective in the
treatment of organic impotence? Results of a controlled trial. Journal of Urology,
137, 1168-1172.
Murphy, M. R., Seckl, J. R., Burton, S., Checkley, S. A., & Lightman, S. L. (1987).
Changes in oxytocin and vasopressin secretion during sexual activity in men.
Nadelhaft, L, & Booth, A. M. (1984). The location and morphology of pregangli-
onic neurons and the distribution of visceral afferents from the rat pelvic
nerve: A horseradish peroxidase study. Journal of Comparative Neurology,
226, 238-245.
Nadelhaft, I., & McKenna, K. E. (1987). Sexual dimorphism in sympathetic pregan-
glionic neurons of the rat hypogastric nerve. Journal of Comparative Neurology,
256, 308-315.
Nygren, L. G., & Olson, L. (1977). A new major projection from locus ceruleus:
The main source of noradrenergic nerve terminals in the ventral and dorsal
columns of the spinal cord. Brain Research, 132, 85-93.
Papka, R. E., McCurdy, J. R., Williams, S. J., Mayer, B., Marson, L., & Platt, K. B.
(1995). Parasympathetic preganglionic neurons in the spinal cord involved in
uterine innervation are cholinergic and nitric oxide-containing. Anatomical
Record, 241, 554-562.
Papka, R.E., Williams, S., Miller, K. E., Copelin, T., & Puri, P. (1998). CNS
location of uterine-related neurons revealed by trans-synaptic tracing with
pseudorabies virus and their relation to estrogen receptor-immunoreactive
neurons. Neuroscience, 84, 935-952.
Park, K., Goldstein, L, Andry, C., Siroky, M. B., Krane, R. J., &. Azadzoi, K. M.
(1997). Vasculogenic female sexual dysfunction: The hemodynamic basis for
vaginal engorgement insufficiency and clitoral erectile insufficiency. Interna-
tional Journal of Impotence Research, 9, 27-37.
Pehek, E. A., Thompson, J. T., & Hull, E. M. (1989a). The effects of intrathecal
administration of the dopamine agonist apomorphine on penile reflexes and
copulation in the male rat. Psychopharmacology (Berlin), 99, 304-308.
Pehek, E. A., Thompson, J. T., & Hull, E. M. (1989b). The effects of intracranial
administration of the dopamine agonist apomorphine on penile reflexes and
seminal emission in the rat. Brain Research, 500, 325-332.
Pescatori, E. S., Engelman, J. C., Davis, G., & Goldstein, I. (1993). Priapism of
the clitoris: A case-report following tradazone use. Journal of Urology, 149,
1557-1559.
Pfaus, J. G., & Gorzalka, B. B. (1987). Opioids and sexual behaviour. Neuroscience
and Biobehavior Reviews, II, 1-34.
Poggioli, R., Arletti, R., Benelli, A., Cavazzuti, E., & Bertolini, A. (1998). Diabetic
rats are unresponsive to the penile erection-inducing effect of intracerebroven-
tricularly injected adrenocorticotropin. Neuropeptides, 32, 151-155.

Pomerantz, S. M., Hepner, B. C., & Wertz, J. M. (1993). Serotonergic influences
on male sexual behavior of rhesus monkeys: Effects of serotonin agonists.
Psychopharmacology (Berlin) , 1 1 1 , 47-54.
Purinton, P. T., Fletcher, T. F., & Bradley, W. E. (1976). Innervation of pelvic
viscera in the rat. Investigative Urology, 14, 28-32.
Rampin, O., Bernabe, J., &. Giuliano, F. (1997). Spinal control of penile erection.
World Journal of Urology, 15, 2-13.
Rattner, W. H., Gerlaugh, R. L., Murphy, J. J., & Erdman, W. J., II. (1958). The
bulbocavernosus reflex: I. Electromyographic study of normal patients. Journal
of Urology, 80, 140-141.
Reid, K., Morales, A., Harris, C., Surridge, D. H., Condra, M., & Owen, J. (1987).
Double blind trial of yohimbine in treatment of psychogenic impotence. Lancet,
2(8556), 421-423.
Ridet, J. L., Tamir, H., & Privat, A. (1994). Direct immunocytochemical localiza-
tion of 5-hydroxytryptamine receptors in the adult rat spinal cord: A light
and electron microscopic study using an anti-idiotypic antiserum. Journal of
Neuroscience Research, 38, 109-121.
Rodriguez'Manzo, G., & Fernandez-Guasti, A. (1994). Reversal of sexual exhaustion
by serotonergic and noradrenergic agents. Behavioral Brain Research, 62,
127-34.
Rose, J. D. (1990). Brainstem influences on sexual behavior. In W. R. Klemm &
R. P. Vertes (Eds.), Brainstem mechanisms of behavior (pp. 407-463). New
York: Wiley.
Saenz de Tejada, I., Ware, J. C., Blanco, R., Pittard, J. T., Nadig, P. W., Azadzoi,
K. M., et al. (1991). Pathophysiology of prolonged penile erection associated
with trazodone use. Journal of Urology, 145, 60-64-
Sagar, S. M., Sharp, F. R., &. Curran, T. (1988). Expression of c-fos protein in
brain: Metabolic mapping at the cellular level. Science, 240, 1326-32.
Saito, S., Kidd, G. J., Trapp, B. D., Dawson, T. M., Bredt, D. S., Wilson, D. A., et
al. (1994). Rat spinal cord neurons contain nitric oxide synthase. Neuroscience,
59, 447-456.
Saper, C. B., Loewy, A. D., Swanson, L. W., & Cowan, W. M. (1976). Direct
hypothalamo-autonomic connections. Brain Research, 117, 305-312.
Sar, M., & Stumpf, W. E. (1975). Distribution of androgen concentrating neurons
in the rat brain. In W. E. Stumpf & L. D. Grant (Eds.), Anatomical neuroendo-
crinology (pp. 120-133). Basel, Switzerland: Karger.
Sato, Y., Christ, G. J., Horita, H., Adachi, H., Suzuki, N., &Tsukamoto, T. (1999).
The effects of alterations in nitric oxide levels in the paraventricular nucleus
on copulatory behavior and reflexive erections in male rats. Journal of Urology,
162, 2182-2185.
Sato, Y., Horita, H., Kurohata, T., Adachi, H., & Tsukamoto, T. (1998). Effect of
the nitric oxide level in the medial preoptic area on male copulatory behavior
in rats. American Journal of Physiology, 274, R243-R247.

Sawchenko, P. E., & Swanson, L. W. (1982). Immunohistochemical identification
of neurons in the paraventricular nucleus of the hypothalamus that project to
the medulla or to the spinal cord in the rat. Journal of Comparative Neurology,
205, 260-272.
Schr0der, H. D. (1980). Organization of the motoneurons innervating the pelvic
muscles of the male rat. Journal of Comparative Neurology, 192, 567-587.
Schr0der, H. D., & Skagerberg, G. (1985). Catecholamine innervation of the caudal
spinal cord in the rat. Journal of Comparative Neurology, 242, 358-368.
Segraves, R. T., Bari, M., Segraves, K., & Spirna, P. (1991). Effect of apomorphine
on penile tumescence in men with psychogenic impotence. Journal of Urology,
145, 1174-1175.
Shimura, T., & Shimokochi, M. (1991). Modification of male rat copulatory behav-
ior by lateral midbrain stimulation. Physiology and Behavior, 50, 989-994.
Simerly, R. B., & Swanson, L. W. (1986). The organization of neural inputs to the
medial preoptic nucleus of the rat. Journal of Comparative Neurology, 246, 312-
342.
Simerly, R. B., & Swanson, L. W. (1988). Projections of the medial preoptic nucleus:
Phaseolus vulgaris leucoagglutinin anterograde tract-tracing study in the rat.
Journal of Comparative Neurology, 270, 209-242.
Sipski, M. L., Alexander, C. ]., & Rosen, R. C. (1985). Orgasm in women with
spinal cord injuries: A laboratory-based assessment. Archives ofPhysicalMedicine
and Rehabilitation, 76, 1097-1102.
Skagerberg, G., & Bjorklund, A. (1985). Topographic principles in the spinal
projections of serotonergic and non-serotonergic brainstem neurons in the rat.
Neurosdence, 15, 445-480.
Skagerberg, G., & Lindvall, O. (1985). Organization of diencephalic dopamine
neurons projecting to the spinal cord of the rat. Brain Research, 342, 340-341.
Skagerberg, G., Bjorklund, A., Lindvall, O., & Schmidt, R. H. (1982). Origin
and termination of the diencephalo-spinal dopamine system in the rat. Brain
Research Bulletin, 9, 237-244.
Slimp, J.C., Hart, B. L., & Goy, R. W. (1975). Heterosexual, autosexual and
social behavior of adult male rhesus monkeys with medial preoptic-anterior
hypothalamic lesions. Brain Research, 142, 105-122.
Steers, W. D., & de Groat, W. C. (1989). Effects of m-clorophenylpiperazine on
penile and bladder function in rats. American Journal of Physiology, 257, R1441-
R1449.
Steers, W. D., Mallory, B., & de Groat, W. C. (1988). Electrophysiological study
of neural activity in penile nerve of the rat. American Journal of Physiology,
254, R989-R1000.
Steinbusch, H. (1981). Distribution of serotonin-immunoreactivity in the central
nervous system of the rat-cell bodies and terminals. Neurosdence, 6, 557-618.
Svensson, L., & Hansen, S. (1984). Spinal monoaminergic modulation of masculine
copulatory behavior in the rat. Brain Research, 302, 315-321.

Swanson, L. W., & Kuypers, H. G. J. M. (1980). The paraventricular nucleus of
the hypothalamus: Cytoarchitectonic subdivisions and organization of projec-
tions to the pituitary, dorsal vagal complex, and spinal cord as demonstrated
by retrograde fluorescence double-labeling methods. Journal of Comparative
Neurology, 194, 555-570.
Szele, P.O., Murphy, D. L, & Garrick, N. A. (1988). Effects of fenfluramine,
mchlorophenylpiperazine, and other serotonin-related agonists and antagonists
on penile erections in nonhuman primates. Life Science, 43, 1297-1303.
Tang, Y., Rampin, O., Galas, A., Facchinetti, P., &Giuliano, F. (1998). Oxytociner-
gic and serotonergic innervation of identified lumbosacral nuclei controlling
penile erection in the male rat. Neuroscience, 82, 241-254-
Tang, Y., Rampin, O., Giuliano, F., & Ugolini, G. (1999). Spinal and brain circuits
to motoneurons of the bulbospongiosus muscle: Retrograde transneuronal trac-
ing with rabies virus. Journal of Comparative Neurology, 414, 167-192.
Tetel, M. J., Getzinger, M. J., & Blaustein, J. D. (1993). Fos expression in the rat
brain following vaginal-cervical stimulation by mating and manual probing.
Theodosis, D. T. (1985). Oxytocin-immunoreactive terminals synapse on oxytocin-
ergic neurons in the supraoptic nuclei. Nature, 313, 682-684.
Thor, K. B., Nickolaus, S., & Helke, C. J. (1993). Autoradiographic localization
of 5-hydroxytryptaminelA, 5-hydroxytryptaminelB and 5-hydroxytrypta-
minelC/2 binding sites in the rat spinal cord. Neuroscience, 55, 235-252.
Truitt, W. A., &. Coolen, L. M. (2002). Identification of a potential ejaculation
generator in the spinal cord. Science, 297, 1566-1569.
Uitti, R. J., Tanner, C. M., Rajput, A. H., Goetz, C. G., Klawans, H. L., &.Thiessen,
B. (1989). Hypersexuality with antiparkinsonian therapy. Clinical Neuro-
Valtschanoff, J. G., Weinberg, R. J., & Rustioni, A. (1992). NADPH diaphorase
in the spinal cord of rats. Journal of Comparative Neurology, 321, 209-222.
Van Bockstaele, E. J., Pieribone, V. A., &. Aston-Jones, G. (1989). Diverse afferents
converge on the nucleus paragigantocellularis in the rat ventrolateral medulla:
Retrograde and anterograde tracing studies. Journal of Comparative Neurology,
290, 561-584.
Van der Ploeg, L. H., Martin, W. J., Howard, A. D., Nargund, R. P., Austin, C. P.,
Guan, X., et al. (2002). A role for the melanocortin 4 receptor in sexual
function. Proceedings of the National Academy of Sciences USA, 99, 11381-
11386.
Van Dis, H., & Larsson, K. (1970). Seminal discharge following intracranial electri-
cal stimulation. Brain Research, 23, 381-386.
Veening, J. G., & Coolen, L. M. (1998). Neural activation following sexual behavior
in the male and female rat brain. Behavioral Brain Research, 92, 181-93.
Veronneau-Longueville, F., Rampin, O., Freund-Mercier, M.-J., Tang, Y., Galas,
A., Marson, L., et al. (1999). Oxytocinergic innervation of autonomic nuclei

Vodusek, D. B. (1990). Pudenda! SEP and bulbocavernosus reflex in women. Electro-
encephalography and Clinical Neurophysiology, 77, 134-136.
Wagner, C. K., & Clemens, L. G. (1991). Projections of the paraventricular nucleus
of the hypothalamus to the sexually dimorphic lumbosacral region of the spinal
cord. Brain Research, 539, 254-262.
Wagner, C. K., & Clemens, L. G. (1993). Neurophysin-containing pathway from
the paraventricular nucleus of the hypothalamus to a sexually dimorphic motor
nucleus in lumbar spinal cord. Journal of Comparative Neurology, 336, 106-116.
Waldinger, M. D. (2002). The neurobiological approach to premature ejaculation.
Journal o/l/roiog}, 168, 2359-2367.
Waldinger, M. D., Berendsen, H. H. G., Blok, B. R, Olivier, B., & Holstege, G.
(1998). Premature ejaculation and serotonergic antidepressants-induced de-
layed ejaculation: The involvement of the serotonergic system. Behavioral Brain
Research, 92, 111-118.
Walsh, P. C., & Donker, P. J. (2002). Impotence following radical prostatectomy:
Insight into etiology and prevention. Journal of Urology, 167, 1005-1010.
Warner, R. K., Thompson, J. T., Markowski, V. P., Loucks, J. A., Bazzett, T. J.,
Eaton, R. C., &Hull, E. M. (1991). Microinjection of the dopamine antagonist
cis-flupenthixol into the MPOA impairs copulation, penile reflexes and sexual
motivation in male rats. Brain Research, 540, 177-182.
Wessells, H., Hruby, V. J., Hackett, J., Han, A. G., Balse-Srinivasan, P., & Vanderah,
T. W. (2003). Ac-Nle-c[Asp-His-DPhe'Arg-Trp-Lys]-NH2 induces penile
erection via brain and spinal melanocortin receptors. Neuroscience, 118, 755-
762.
Wessels, H., Fuciarelli, K., Hansen, J., Hadley, M. E., Hruby, V. J., Dorr, R., &
Levine, N. (1998). Synthetic melanotropic peptide initiates erections in men
with psychogenic erectile dysfunction: Double blind, placebo controlled cross-
over study. Journal of Urology, 160, 389-393.
Wessels, H., Levine, N., Hadley, M. E., Dorr, R., & Hruby, V. (2000). Melanocortin
receptor agonists, penile erection, and sexual motivation: Human studies with
Melanotan II. International Journal of Impotence Research, 12(Suppl 4), S74-S79.
Whipple, B., Richards, E., Tepper, M., & Komisaruk, B. R. (1995). Sexual responses
in women with complete spinal cord injury. In D. M. Krotosku, M. Nosek, &
M. Turk (Eds.), The health of women with physical disabilities: Setting a research
agenda for the 90's. Baltimore: Paul H. Brookes.
Wikberg, J. E . (1999). Melanocortin receptors: Perspectives for novel drugs. Euro-
pean Journal of Pharmacology, 375, 295-310.
Wikberg, J. E., Muceniece, R., Mandrika, L, Prusis, P., Lindblom, J., Post, C., &
Skottner, A. (2000). New aspects on the melanocortins and their receptors.
Pharmacological Research, 42, 393-420.
Yanagimoto, M., Honda, K., Goto, Y., & Negoro, H. (1996). Afferents originating
from the dorsal penile nerve excite oxytocin cells in the hypothalamic para-
ventricular nucleus of the rat. Brain Research, 733, 292-296.

Yang, S. P., & Voogt, J. L. (2001). Mating-activated brainstem catecholaminergic
neurons in the female rat. Brain Research, 894, 159-166.
Yells, D. P., Hendricks, S. E., & Prendergast, M. A. (1992). Lesions of the nucleus
paragigantocellularis: Effects on mating behavior in male rats. Brain Research,
596, 73-79.
Zorgniotti, A. W. (1992). "On demand" erection with oral preparations for impo-
tence: 3- (N- (2-imidazoline-2ylmethyl) -p-toluidinol) phenol mesylate. Inter-
national Journal of Impotence Research, 4(Suppl 2), A99.
Zorgniotti, A. W. (1994). Experience with buccal phentolamine mesylate for impo-
tence. International Journal of Impotence Research, 6, 37-41.
Zorgniotti, A. W., & Lizza, E. F. (1994). Effect of large doses of the nitric oxide
precursor, L-arginine, on erectile dysfunction. International Journal of Impotence
Research, 6, 33-35.

BRAIN ACTIVITY IMAGING DURING
SEXUAL RESPONSE IN WOMEN WITH
SPINAL CORD INJURY
BARRY R. KOMISARUK AND BEVERLY WHIPPLE
The present series of brain-imaging studies was initiated in response

to intriguing early reports that women diagnosed with "complete" spinal
cord injury may experience orgasms during sexual intercourse (Cole, 1975;
Kettl et al, 1991; Whipple, 1990), more recent laboratory confirmatory
reports (Komisaruk & Whipple, 1994; Sipski & Alexander, 1995; Sipski,
Alexander, & Rosen, 1995; Whipple, Gerdes, & Komisaruk, 1996), and a
report that pregnant women with spinal cord injury below T12 can feel
uterine contractions and movement of their fetus in utero (Berard, 1989).
The reports are surprising because the genital sensory pathways that ascend
from the genitalia to the brain are presumably interrupted by the spinal
cord injury. According to the diagnosis of complete spinal cord injury,
It is with the deepest gratitude that we acknowledge our expert collaborators on the brain imaging
project: for the positron emission tomography studies, John W. Keyes, Beth Harkness, and Carolyn
Gerdes; and for the functional magnetic resonance imaging studies, Kris Mosier, Andrew Kalnin,
Wen-Ching Liu, Audrita Crawford, and Sherry Grimes. Funding support was from The Christopher
Reeve Paralysis Foundation, National Institutes of Health (Grant R25GM60826), and The Charles
and Johanna Busch Foundation, Rutgers, The State University of New Jersey.
109
women do not have sensibility below the level of the injury. Indeed, as
some of the women in the studies that we describe in this chapter reported
to us, their physicians told them that their "sensations" are imaginary, a
reply that they said upset them.1
On the basis of descriptions of the peripheral distribution and level
of entry into the spinal cord of the genital sensory nerves in women (Bonica,
1967), and our and others' mapping of the sensory fields and zones of entry
into the spinal cord of the genital sensory nerves in the female rat (Berkley,
Hotta, Robbins, & Sato, 1990; Cunningham, Steinman, Whipple, Mayer,
& Komisaruk, 1991; Komisaruk, Adler, & Hutchison, 1972; Kow & Pfaff,
1973-1974; Peters, Kristal, & Komisaruk, 1987; see also McKenna, chap.
4, this volume), we suspected that the location along the course of the
spinal cord at which the injury occurred is critical. We hypothesized that
some genital sensation could occur even if the complete spinal cord injury
extended as high as spinal cord thoracic level 11. We formulated this
hypothesis on the basis that the hypogastric nerves ascend in the sympathetic
chain and enter the spinal cord at thoracic levels 10-12 (Bonica, 1967;
Felten & Jozefowicz, 2003).
BACKGROUND
To provide context and rationale for the brain imaging studies described
below, we first describe the classic picture of the different nerves that
innervate the specific genital regions.
The division of labor among the genital sensory nerves is basically as
follows. The hypogastric nerves convey sensory activity from the uterus and
cervix in women (Bonica, 1967) and in rats (Berkley et al., 1990; Peters
et al., 1987); the pelvic nerves convey sensory activity from the cervix,
vagina, and midline perineal skin (Berkley et al., 1990; .Komisaruk et al.,
1972; Peters et al., 1987); and the pudendal nerves convey sensory activity
from the clitoris and perineal skin (Peters et al., 1987). Thus, hypogastric
nerve fibers that enter the spinal cord at T10, directly above a complete
injury as high as Tl 1, could conceivably convey some genital sensory activity
that could access the brain and hence attain perceptibility. The pudendal
and pelvic nerves enter the spinal cord at upper sacral and lower lumbar
levels (Ding et al., 1999).
1
The clinical diagnosis of "complete" spinal cord injury is based on criteria by the American Spinal
Injury Association (1992) of absence of sensation of pinprick (pain) or cotton wisp (touch) and
absence of voluntary movement, all below the level of the injury, plus the absence of sensation of
rectal digital stimulation.
110 KOMISARUK AND WHIPPLE

Laboratory Study of Women With Complete Spinal Cord Injury at
Specific Levels
From the above considerations, it is reasonable to infer that cervical

stimulation, accessing the brain via activation of the hypogastric nerves,
might be sufficient to elicit orgasm. To test this hypothesis and assess the
division of labor among the genital sensory nerves, we analyzed perceptual
responses to genital self-stimulation in women who were diagnosed with
complete spinal cord injury that was between the level of entry of the
hypogastric and pelvic-pudendal nerves (thereby allowing access to the brain
of the former but not the latter). We compared this group with able-bodied
women and women diagnosed with complete spinal cord injury at or above
T10. We hypothesized that this latter group would show no responses to
vaginal or cervical self-stimulation. However, to our surprise, rather than
showing no responses, the women with complete spinal cord injury at or
above T10 showed the strongest responses to the vaginal or cervical self-
stimulation, compared with the other two groups of women. Our unexpected
findings led us to hypothesize that genital sensory responses in these women
can be conveyed via the Vagus nerves (Komisaruk & Whipple, 1994; Komi-
saruk, Gerdes, & Whipple, 1997; Whipple et al., 1996). We have tested
this hypothesis by using functional brain imaging methodology—positron
emission tomography (PET) and functional magnetic resonance imaging
(fMRI)—to ascertain whether cervical self-stimulation would activate the
sensory projection nucleus of the Vagus nerve in women with complete
injury to, or transection of, the spinal cord (Komisaruk, Whipple, et al.,
2002; Whipple & Komisaruk, 2002).
The Vagus Nerves
The findings that led us to hypothesize a genital sensory role for the
Vagus nerves were as follows. We used several measures to ascertain responses
to vaginal or cervical self-stimulation. In addition to assessing the amount
of force at which the women reported they could feel the stimulator pressing
against the cervix (Komisaruk, Gerdes, & Whipple, 1997), whether they
experienced sexual responses or orgasm from the stimulation (Whipple et
al., 1996), and, independently of the laboratory setting, whether they per-
ceived menstrual discomfort, we also obtained an objective measure—pain
thresholds—measured at the fingers.2
2
Why measure pain thresholds? Our previous studies in the laboratory rat showed that vaginocervical
pressure produces a pain blockage so effective that the rats do not withdraw from the painful
stimulus (e.g., an intensely hot lamp) beyond the point at which they would sustain tissue damage
(Komisaruk et al., 1996). During natural mating, the female rat's pain threshold increases to a level
more than that produced by three times the analgesic dose of morphine (Gomora, Beyer, Gonzalez-
BRAIN ACTIVITY IMAGING 111

We measured pain thresholds before, during, and after cervical self-
stimulation by applying a calibrated, gradually increasing force via a l-miri'
tip diameter plastic rod to the fingers up to a maximum force of 1 kg. We
recorded the force at which the participant reported that it felt painful,
which we took as the pain-detection threshold. We also measured tactile
thresholds using a calibrated, graded series of von Frey fibers applied to the
dorsal surface of the hand (Komisaruk, Gerdes, & Whipple, 1997; Whipple
& Komisaruk, 1985, 1988).
Rationale for the Research Methodology Used
The basis for using these pain and touch threshold determinations was
as follows. We had shown previously (Komisaruk & Whipple, 1984; Whipple
& Komisaruk, 1985) that when noninjured women applied a steady force
against the anterior vaginal wall ("Grafenberg spot"), their pain detection
thresholds increased by an average of more than 50% over control, resting
baseline levels. At the same time, the tactile thresholds showed no significant
change. When the women in that study applied vaginal self-stimulation in
a manner that they reported felt pleasurable, their average pain detection
threshold increased more than 75%, with no significant change in tactile
thresholds. Four of the 10 women in the study experienced orgasm during
the vaginal self-stimulation, and under that condition, the average pain
detection threshold increased by more than 100% over the resting-control
baseline levels, and again, there was no significant change in tactile thresh-
olds (Whipple & Komisaruk, 1985). A typical subjective report by the
women was that they were aware of the increasing compressive force on
their fingers, but it did not bother them until it actually became painful
(but at that point the average compressive force averaged at least 50%
greater than before the vaginal self-stimulation). Thus, the women were
fully aware of the testing situation at all times, suggesting that the
elevation in pain thresholds was not due to distraction. Another line of
evidence that they were not distracted from the test situation by the
vaginal self-stimulation is that they provided reports on their (unchanging)
Mariscal, & Komisaruk, 1994), and during parturition—the other event when vaginocervical
pressure stimulation occurs normally—pain thresholds are also increased (Toniolo, Whipple, &
Komisaruk, 1987).
We speculate that the function of this pain blockage during (a) parturition is to attenuate the
stress of parturition and facilitate bonding between mother and young and (b) mating, to render the
female willing to accept the multiple intromissions that are necessary to stimulate the secretion of
levels of progesterone that are necessary to prepare the uterus for implantation of the fertilized ova.
These findings led us to test and demonstrate that a comparable phenomenon of pain blockage in
response to vaginal or cervical stimulation exists in women (for review, see Komisaruk & Whipple,
1995).
I12 KOMISARUK AND WHIFFLE

tactile sensitivity continually throughout the testing period, including
the time when they were applying the vaginal self-stimulation (Whipple
& Komisaruk, 1985).
In a second study, we used additional methods to assess the possibility
that distraction could account for the findings; that is, the participants
watched the train-chase scene from the film, The French Connection, or they
brushed a fur mitt in a pleasurable manner against their skin, while pain
thresholds and tactile thresholds were measured. Although a significant
increase in pain detection thresholds during vaginal self-stimulation was
again observed in this study, there was no significant effect of any of the
distracting stimuli on pain detection thresholds and no change in tactile
thresholds (Whipple &. Komisaruk, 1985). From these findings we concluded
that vaginal self-stimulation produces analgesia, that is, a selective attenua-
tion of pain but not touch. After completion of the day's testing, when
each woman was asked what she thought we were testing, almost all answered
that we were trying to ascertain whether pain interferes with sexual response.
Because this is the opposite of what we were actually testing, it is also
unlikely that their preconceptions led to bias in an expectation of analgesia.
Indirect Evidence Supporting a "Genitosensory Vagus" Hypothesis
Returning to consideration of our study on responses to cervical self-

stimulation in women with complete spinal cord injury (Komisaruk, Gerdes,
& Whipple, 1997; Whipple et al., 1996), the control group in that study
consisted of 5 women without spinal cord injury. The experimental groups
consisted of 10 women with complete spinal cord injury below T10 and 6
women with complete spinal cord injury above the level of entry into the
spinal cord of all three pairs of these nerves (i.e., complete injury at T10
or above). We expected that the women in the latter group (i.e., complete
injury at T10 or above) would show no response to the self-stimulation.
We measured pain detection thresholds and tactile thresholds as in our
previous studies in women. Our unexpected and surprising finding was that,
contrary to our expectation that the women with complete spinal cord
injury at T10 or above would fail to respond to the self-stimulation, the
women with this highest level of spinal cord injury actually had the strongest
analgesic responses to vaginal or cervical self-stimulation among the three
groups. All 6 of the women also stated that they commonly experienced
menstrual discomfort, which originated from below the level of their spinal
cord injury. One of the 6 women in this group reported several orgasms in
the laboratory during the cervical self-stimulation. Four of the 6 women
were able to feel the stimulator when it was pressed against the cervix,
although the force threshold for their feeling it was significantly higher than

that in the noninjured women (Komisaruk, Gerdes, &. Whipple, 1997;
Komisaruk & Whipple, 1994; Whipple et al., 1996).
Evidence for a "Genitosensory Vagus" Based on Studies in

Laboratory Animals
To account for this finding—and on the basis of a report in rats by

Guevara-Guzman and colleagues (Ortega-Villalobos et al., 1990) that the
neural tracer, horseradish peroxidase, when injected into the cervix produced
labeling of neurons in the nodose ganglion, which is the dorsal root (i.e.,
sensory) ganglion of the Vagus nerve—we hypothesized that in the women
with complete spinal cord injury, the basis for their perceptual responses to
the cervical self-stimulation was that the Vagus nerves were providing the
sensory pathway for the cervical stimulation to reach the brain. The innerva-
tion of the uterus and cervix by the Vagus nerves in the rat was subsequently
confirmed by Papka and colleagues (Collins, Lin, Berthoud, & Papka, 1999).
Vagal electrical stimulation has been shown to produce analgesia in rats
(Maixner & Randich, 1984; Ness, Randich, Fillingim, Faught, & Backensto,
2001; Randich & Gebhart, 1992) and in humans (Kirchner, Birklein, Stefan,
& Handwerker, 2000), and we reported that vaginocervical probing in rats
produces analgesia even after bilateral transection of the known genitospinal
nerves (pudendal, pelvic, and hypogastric). That analgesia is abolished after
subsequent bilateral transection of the Vagus nerves (Bianca et al., 1994;
Cueva-Rolon et al., 1994, 1996).
We tested the Vagus nerve hypothesis in rats using two different
approaches: transecting the known genitospinal nerves or transecting the
spinal cord, followed by testing for persistence of any responses to vaginocer-
vical stimulation (VCS), followed by bilaterally transecting the Vagus nerves
and subsequent retesting for responses to VCS. VCS produced analgesia
after bilateral transection of the pudendal, pelvic, and hypogastric nerves,
although the magnitude of the analgesia was lower than in the intact
rats; subsequent bilateral transection of the Vagus nerves in the abdomen
abolished this analgesia (Cueva-Rolon et al., 1994, 1996).
In a separate study, we found that significant pupil dilatation in response
to VCS persisted, although at a diminished magnitude, after total surgical
ablation of the spinal cord at the mid-thoracic level (T7) of the spinal cord
in rats. Subsequent bilateral transection of the Vagus nerves in the abdomen
abolished the pupil dilatation response to VCS (Komisaruk, Bianca, et
al., 1996).
As a further test of this Vagus nerve hypothesis, we transected one of
the pair of Vagus nerves in the neck and stimulated a central end electrically.
We observed an immediate and marked pupil dilatation, thus supporting

our hypothesis that vagal afferent activity stimulates pupil dilatation (Komi'
saruk et al., 1996).3
Hypothesis
Our hypothesis is that vaginocervical self'Stimulation in women with

total interruption of the spinal cord will activate the brain region to which
the Vagus nerve directly projects. The sensory fibers of the Vagus nerves
pass totally outside the spinal cord, through the abdominal cavity, the
diaphragm, the thoracic cavity, and the neck. The primary afferent terminals
of these fibers project' directly to the nucleus of the solitary tract (NTS),
which is situated in the medulla oblongata of the lower brainstem. Thus,
the NTS is the site of the first synapse between the sensory fibers of the
Vagus nerve and the central nervous system. Hubscher and Berkley (1994,
1995) reported that neurons of the NTS in rats responded to mechanical
stimulation of the vagina, cervix, uterus, or rectum, and vagotomy altered
these responses. On the basis of the above studies, we concluded that the
Vagus nerves constitute a functional afferent pathway from the vagina
and cervix that bypasses the spinal cord, projecting directly to the brain,
specifically to the NTS of the lower brainstem (Komisaruk, Gerdes, &
Whipple, 1997; Komisaruk & Whipple, 1994, 2000; Whipple et al., 1996).
NEW RESEARCH FINDINGS: TESTING THE HYPOTHESIS
To test whether the NTS is activated by vaginocervical self'Stimulation

in women with the highest level of complete spinal cord injury and in
noninjured women, we have used positron emission tomography (PET) with
O15-labeled water as the tracer (Komisaruk, Whipple, Gerdes, Harkness, &
Keyes, 1997) and functional magnetic resonance imaging (fMRI; Komisaruk,
Whipple, et al., 1996, 1997, 2002; Whipple & Komisaruk, 2002). The
resolution of the PET method appears to be too low to localize responses
in the medulla. As an alternative, we have found that the fMRI method
has higher resolution plus adequate sensitivity to show brain responses to
3
There is a possible source of confusion regarding the Vagus nerve as a parasympathetic nerve and
the fact that parasympathetic stimulation constricts, rather than dilates, the pupil. There is,
however, no contradiction with the present findings, for neither of these considerations is relevant
to the present findings. That is, first, the parasympathetic innervation of the eye is via the
oculomotor nerve (cranial nerve III) rather than the Vagus. And second, it is afferent, not efferent,
activity of the Vagus nerve that is producing the pupil dilatation. Thus, Vagus nerve afferent
activity, via stimulation of its central nervous system projection pathways, has the capacity to
stimulate a sympathetic-dominated response of the pupil.

genital self-stimulation. Using the fMRI method, we have obtained evidence
that cervical self-stimulation produces activation of NTS in women with
complete spinal cord injury above T10. These findings support our hypothesis
that the Vagus nerve provides a spinal cord bypass pathway in women for
afferent activity generated by cervical self-stimulation.
The PET Method: Findings, Advantages, and Limitations
Despite the relatively low resolving power of the PET method, we

have nevertheless observed activation in what appears to be the region of
the para ventricular nucleus (PVN) of the hypothaiamus in a noninjured
woman during orgasm that she induced by cervical self-stimulation. Our
subsequent studies using fMRI have confirmed this response in additional
women. These findings are consistent with reports of release of oxytocin
into plasma during orgasm in women (Blaicher et al., 1999; Carmichael et
al., 1987; Carmichael, Warburton, Dixen, & Davidson, 1994).
Figures 5.1 through 5.3 show schematically our hypothesis of the
location of the neural pathways that mediate vaginal or cervical self-
stimulation-induced analgesia, measured at the fingers, in women with intact
or transected spinal cord. In Figure 5.1, the radial nerve conveys noxious
sensory input to the spinal cord at the cervical level, where it synapses on
second-order neurons of the spinothalamic system and then on third-order
neurons that project from thalamus to cortex.
Figure 5.2 is based on the likelihood of similarity with the endogenous
analgesia-producing system in rats (reviewed in Komisaruk & Whipple,
2000). This illustration depicts our concept of a system by which genitospinal
afferents via the pelvic and hypogastric nerves synapse first in the spinal cord
and then project to the lower brainstem, where they stimulate descending
noradrenergic (NE) and serotoninergic (5-HT) pathways that generate pre-
synaptic inhibition of the primary afferents of the radial nerve. This would
result in inhibiting the release of pain transmitters and blocking the nocicep-
tive activity.
Figure 5.3 shows the proposed vagal afferent pathway that bypasses
the spinal cord, terminates in the NTS in the medulla oblongata, which is
the vagal sensory nucleus, and stimulates the same descending pathway to
block the nociceptive input at the primary afferent terminals of the radial
nerve in the cervical level of the spinal cord.
We hypothesized that in the women with complete interruption of
the spinal cord, cervical self-stimulation produces analgesia by activating
the Vagus nerves, and consequently that the NTS would be activated by
this stimulation. We first used PET with O15-labeled water as the tracer
and superimposed the PET activity images on anatomical MRI to enable
neuroanatomical localization of the activity. The principle of action of this

Finger pain pathway
• ••»
gastrrc nerve
Figure 5.1. Neural pathway for finger pain.
method is that the more active a cluster of neurons becomes, the greater
is the amount of blood that becomes supplied to that cluster, and thus, the
greater is the amount of radioactivity per unit time in the region of the
cluster. A greater concentration of radioactivity in a brain region appears
as a brighter region in the images (these images use a "hot-metal" gradient
representation, in which dark red is "coolest," representing lowest radioactiv-
ity, and yellow-white is "hottest," representing highest radioactivity).
Figure 5.4 shows the activity in the region of the NTS during cervical
self-stimulation in a woman with complete spinal cord injury at T8. There

Vaginal-cervical self-stimulation attenuates finger pain
PAIN ATTENUATED
hypogastric nerve
Figure 5.2. Presumptive genitospinal neural pathways mediating pain attenuation.

NE = noradrenergic pathway; 5-HT = serotoninergic pathway.
are two control conditions: the first, resting with no cervical self'Stimulation,
and the second, application of heated vibrators to both feet simultaneously.
Note that in the region delineated by the oval, there is no visible activity
during the resting control condition. Furthermore, in the foot stimulation
control condition, there is little or no visible activity. The rationale for this
control condition is that the modalities of touch, pressure, vibration, and
heat are all stimulated concurrently, and absence of activation of the thala-
mus would confirm the completeness of spinal cord injury. Analysis of the

Evidence that the Vagus nerves also convey
vaginal-cervical sensory activity
PAIN ATTENUATED
Vagus nerve
"complete" spinal cord
hypogastric nerve
Figure 5.3. Proposed spinal-cord-bypass pathway through which pain is attenuated

by vaginocervical stimulation.
thalamic activity did in fact show little or no activation, by contrast with

a noninjured woman subjected to the same stimulation. By contrast with
these two control conditions, there is substantial activity in the delineated
region (NTS) during cervical self-stimulation. A similar response was
obtained in a second woman with complete spinal cord injury at T9 (Komi-
saruk, Whipple, et al, 1996; Whipple & Komisaruk, 2002). A major limita-
tion of the PET method is its relatively low resolving power. That is, we

NTS RESPONSE TO CERVICAL SELF-STIM.
Complete Spinal Cord Injury at T8
COMBINED MRI - PET SCANS

Subject #233/1298
Transaxial view
MRI CONTROL (No Stimulation)
FOOT STIM CERVICAL SELF-STIM
Figure 5.4. Positron emission tomography (PET) imaging of brainstem response to

cervical self-stimulation in a woman with complete spinal cord injury at T8. The white
ovals encircle the same region of the brain in each image. The upper left image is
the anatomical image of the brain; the other three are the PET images. Note that the
highest activity occurred during cervical self-stimulation. NTS = nucleus of the solitary
tract; STIM = stimulation; MRI = magnetic resonance imaging.
can see that the general region of the NTS in the medulla is active, but
we cannot localize the region of activity restricted to the NTS.
Nevertheless, the resolving power of the PET method was adequate
to enable visualization of heightened activity in certain larger brain regions
in the case of a noninjured woman who experienced an orgasm during the
scan. In this case we observed heightened activity in the midbrain reticular
120 KOM1SARUK AND WH1PPLE

MIDBRAIN RETICULAR FORMATION
MRI Resting Foot stim Cervical self-stim
IR=2.15 2.88
Subject #1414 Non-injured
Figure 5.5. Positron emission tomography (PET) imaging of midbrain reticular

formation during orgasm and control conditions in an uninjured woman. The circles
are located at the same region in each of the images. The arrows in the anatomical
images in the leftmost column point to the same region. Note that the highest activity
occurred during cervical self-stimulation. The top row is a transaxial view, the middle
row a sagittal view, and the bottom row a coronal view, all of the same brain region.
MRI = magnetic resonance imaging; stim = stimulation; IR = the ratio of the quantified
image intensity in the region of interest (delineated by a circle) to that in an adjacent
control brain region (white matter) in each same image. The same conventions are
used here as in Figures 5.6 and 5.7, following.
formation (which others, using PET, have found to show increased activity
during arousal; Balkin et al., 2002), basal ganglia (particularly the region
of the putamen), and anterior hypothalamus in the region of the PVN
(Figures 5.5, 5.6, and 5.7). The format of these figures shows the MRI
anatomical brain "slice" (from top to bottom at the leftmost portion of the
figures) in transaxial (i.e., horizontal), sagittal, and coronal orientation,
respectively. The corresponding activity patterns are shown during the con-
trol resting period, foot stimulation, and cervical self-stimulation, respec-
tively, from the left to the right side of each figure. The intensity of activity
is depicted using the "hot metal" representation. The numerical values
shown at the bottom of each set are the ratios between the activity in the
"region of interest" shown as a circle in each slice and the activity in a

Figure 5.6. Positron emission tomography (PET) imaging of the basal ganglia during
orgasm and control conditions in an uninjured woman. MRI = magnetic resonance
imaging; stim = stimulation; IR = the ratio of the quantified image intensity in the
region of interest to that in an adjacent control brain region in the same image.
control, equivalent-sized region of white matter in the same "slice." All the
circles in each figure—MRI and PET—are in registration with each other;
that is, they all circumscribe the same brain region, regardless of the orienta-
tion of the slices. Note that the ratios are highest during orgasm.
It is perhaps not surprising that the midbrain reticular formation and
the basal ganglia are most active during orgasm, for they are involved in
general arousal and in gross motor control, respectively. However, it was
unexpected, but is particularly interesting, that the region of the hypothala-
mic PVN shows high activity. Oxytocin is synthesized in neurons of the
PVN and is transported through the axons of these neurons, to the axon
terminals in the posterior pituitary gland (i.e., the neurohypophysis; for a
review, see, e.g., Cross & Wakerley, 1977). There, the oxytocin is released
by conventional action potential activity from the axon terminals of these
"neuroendocrine neurons" into the systemic circulation. Several studies have
reported that oxytocin levels in the systemic circulation rise significantly
during orgasm in women and men (Blaicher et al., 1999; Carmichael et al.,
122 KOMISARL/K AND WH1PPLE

PARAVENTRICULAR NUCLEUS
of HYPOTHALAMUS
MRI Resting Foot stim Cervical self-stim
Subject #1414 Non-injured IR=1.39 1.21
Figure 5.7. Positron emission tomography (PET) imaging of the hypothalamus during
orgasm and control conditions in an uninjured woman. MRI = magnetic resonance
imaging; stim = stimulation; IR = the ratio of the quantified image intensity in the
region of interest to that in an adjacent control brain region in the same image.
1987, 1994). We have reported in rats that VCS immediately releases

oxytocin into the systemic circulation (and into the spinal cord; Sansone
et al., 2002). It has been suggested that one of the functions of the oxytocin
in the systemic circulation is to stimulate contractions of the uterus, which
facilitate the transport of seminal fluid through an inward (i.e., toward the
uterus) suction effect (Wildt, Kissler, Licht, & Becker, 1998). These data
are the first of which we are aware providing direct evidence that the PVN
is activated during orgasm.
fMRI: A Higher Resolution Brain Imaging Method
To ascertain whether the NTS is activated by cervical self-stimulation

in women who have complete spinal cord injury above the level of entry
into the cord of the genitospinal nerves (i.e., the pudendal, pelvic, and
hypogastric nerves), we needed a functional brain imaging method that has
higher resolving power than the PET method. We first established the
greater resolving power of the fMRI method in the lower brainstem by

Figure 5.8. Functional magnetic resonance imaging (fMRI) can resolve activity in
localized brain regions: Activation of the region of the hypoglossal nucleus by
tongue movement.
mapping cranial nerve nuclei in the vicinity of the NTS. For example, the
hypoglossal nucleus, which is also in the medulla oblongata, controls tongue
movement. Tapping the tongue against the roof of the mouth produced
activation in the precise location of the hypoglossal nucleus (based on
histological atlases; Figure 5.8), convincing us that the resolving power of
the fMRI method is far better than that of the PET method, and that it is
adequate to localize the NTS (Komisaruk, Mosier, et al., 2002).
fbARI Evidence
To aid in ascertaining the location of the NTS on the fMRI images,
we used existing evidence that the upper (i.e., superior) level of the
NTS conveys taste sensory activity (Travers & Norgren, 1995) by having
the research participants taste a sauce that combined sweet, salty, sour,
and bitter qualities, by combining sugar, salt, lemon juice, and dry mustard,
and mapped the region of activation, an example of which is shown in
Figure 5.9. We then asked two women with complete spinal cord injury
above T10 to perform cervical self-stimulation, after having tasted the sauce.
Figure 5.10 shows an MRI of the spinal cord injury in the first woman. The

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fMRI of the woman (Figure 5.9) shows the anatomical location of the
NTS based on histological atlases, and also shows in sagittal (top) and
coronal (bottom) views the regions activated by taste and by cervical self-
stimulation, respectively.
Figures 5.11 and 5.12 show, for the second woman, the comparable
spinal cord injury site and brain regions activated. Note that in both cases,
the region activated by taste was directly above (superior to) the region
activated by cervical self-stimulation. This provides the first direct evidence
that cervical self-stimulation activates the NTS, thus supporting our hypoth-
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whose afferent pathways through the spinal cord are interrupted.
fMRI Data
The two women with complete spinal cord injury above T10 reported
that they experienced orgasms during the cervical self-stimulation. There
were marked changes in activity in widespread regions of the brain at the
time of the orgasms. Figure 5.13 provides an overall view of the activity in
the brain at the beginning of cervical self-stimulation compared, in Figure
5.14, with the activity of the same brain regions at orgasm. Note the much
greater activation in the lower brainstem, frontal cortex, and cerebellum.
Figure 5.15 shows, at two different imaging criteria (p < .05, dots, and
p < .01, which has a higher threshold for significance of response), that
brain regions activated during orgasm included hypothalamus, amygdala,
cingulate cortex, and insular cortex. The images at the left of this figure
show the MRI anatomical image of the same brain, on which the activity
is superimposed, and at the far left, an atlas image of the same brain region,
based on histological specimens, which aids in the anatomical identification
of the structures.
Figure 5.16 shows fMRI images at two different brain regions, the
hypothalamus (upper and lower images on the right) and, rostral to that,
the preoptic/bed nucleus of the stria terminalis region (upper and lower
images on the left). The upper images show the fMRI activity at orgasm,
and the lower images show the same activity superimposed on the corres-
ponding brain anatomy. Note the activation in the region of the PVN of
the hypothalamus, amygdala, cingulate cortex, insular cortex, and region
of the nucleus accumbens.
Figure 5.17 shows fMRI activity in the region of the PVN of the
hypothalamus during orgasm. The schematic view on the right shows Netter's
diagram (Felten &. Jozefowicz, 2003) of this region, locating the PVN to
the left and slightly below the anterior commissure. The anatomical MRI
image shows the comparable region, the crosshairs identifying the anterior
commissure. The image to the right shows the fMRI activity at orgasm

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134 KOMISARUK AND WHIFFLE

superimposed on this anatomical image. The two lower images show the
fMRI only at the beginning of cervical self-stimulation (left) and at orgasm
(right). Note the activation in the region of the PVN only at orgasm.
Figure 5.18 shows a greater activation of hippocampus at orgasm (pix-
els) than at the onset of cervical self-stimulation. The anatomical image
shows the region of the hippocampus (oval), the superimposed fMRI activity
at orgasm (image to its right), and the fMRI activity only before and during
orgasm (lower and upper figures to the right, respectively).
DISCUSSION
The above findings, based on observation of brain activity, provide

the first evidence to account for the intriguing reports that women with
complete spinal cord injury can perceive genital sensory activity. The find-
ings provide evidence of the mediating neural pathway and are, to our
knowledge, also the first report of brain regions activated during orgasm
in women.
The Vagus Nerves Convey Genital Sensory Activity in Women
The present findings of activation in the region of the NTS in women

with complete spinal cord injury or total interruption of the spinal cord
(verified anatomically using MRI) provide evidence that the NTS is acti-
vated by self-stimulation of the cervix (at the vaginal-uterine junction) in
women who have complete spinal cord injury or total interruption of the
spinal cord above the level of entry into the spinal cord of all the known
genitospinal nerves. As in the case of the women in our previous study with
complete spinal cord injury at comparable levels, these women reported
that they experience menstrual discomfort, responded to cervical self-
stimulation in a typical way by showing analgesia, and could perceive when
the stimulator was pressed against the cervix, although their threshold of
sensibility to this stimulus was significantly higher than that of women
without spinal cord injury.
The Vagus nerves in women provide a genital sensory pathway that
projects directly to the brain, bypassing the spinal cord, and consequently,
spinal cord injury at any level. This pathway can, in some women with
complete spinal cord injury, generate orgasm. We interpret these findings
to support our hypothesis that the Vagus nerves, which project to the NTS,
directly convey the afferent activity from the cervix, and thereby provide
a sensory pathway from the cervix to the brain, bypassing the spinal cord.
Sexual response including orgasm has also been reported by Sipski et
al. (1995) in women with complete spinal cord injury at the levels tested
BRAIN ACTIVITY IMAGING ] 35

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in the present study, and at higher spinal cord levels. Because the Vagus
nerves enter the brain directly, this pathway could account for the findings
in their study. Sipski et al. speculated that "autonomic pathways" mediate
the effect, yet they provided no evidence to support that conclusion. More-
over, they have not explicitly refuted our earlier evidence (Komisaruk &.
Whipple, 1994) that the Vagus nerves could provide an afferent pathway
from the genitalia that would bypass the spinal cord at any level, including
those that they report.
Multiple Brain Regions Are Activated During Orgasm in Women
The brain regions activated during orgasm that was elicited by cervical
self-stimulation include hypothalamus, limbic system (including amygdala,
hippocampus, cingulate cortex and insular cortex, and the region of the
accumbens-bed nucleus of the stria terminalis-preoptic area), neocortex
(including parietal and frontal cortices), basal ganglia (especially putamen),
and cerebellum, in addition to lower brainstem (central gray, mesencephalic
reticular formation, and NTS). Differences between regional activation
during, versus before or after, orgasm suggest that areas more directly related
to orgasm include paraventricular area of the hypothalamus, amygdala, an-
terior cingulate region of the limbic cortex, and region of the nucleus
accumbens. There is no evidence of orgasm in female rats. However, some
of the same brain regions have been reported to become activated during
mating or VCS. Thus, using the c-fos immunocytochemical method, act-
ivation was reported in amygdala (Erskine & Hanrahan, 1997; Pfaus &
Heeb, 1997; Rowe & Erskine, 1993; Tetel, Getzinger, & Blaustein, 1993;
Veening & Coolen, 1998; Wersinger, Baum, & Erskine, 1993), PVN
(Pfaus & Heeb, 1997; Rowe & Erskine, 1993), medial preoptic area (Erskine
& Hanrahan, 1997; Tetel et al., 1993; Wersinger et al., 1993), midbrain
central gray (Pfaus & Heeb, 1997; Tetel et al., 1993), and based on local
release of dopamine, the nucleus accumbens (Pfaus, Damsma, Wenkstern,
& Fibiger, 1995).
First Identification of Brain Regions Activated

During Orgasm in Women
To our knowledge, this is the first evidence of activation of hypothala-

mus during orgasm in men or women. Earlier reports of orgasm in men
found activation in prefrontal cortex but not subcortical structures (Tiihonen
et al., 1994). Also in men, Holstege and colleagues (Holstege et al., 2003)
reported that the mesodiencephalic area, cerebellum pontine reticular forma-
tion, basal ganglia (putamen and claustrum), and several cortical regions
including the lateral prefrontal cortex, but not the hypothalamus, were

activated during orgasm. Furthermore, in men during sexual arousal, but not
orgasm, elicited by photographs, Wallen and colleagues (Hamann, Herman,
Nolan, & Wallen, 2002) reported that fMRI activity was increased in
amygdala, hippocampus, and hypothalamus compared with the activity in
women, whereas the striatal regions (caudate and nucleus accumbens) were
activated in both men and women.
The findings in the present study of activation of PVN, observed using
PET as well as fMRI, are consistent with reports of oxytocin release during
orgasm. That is, the PVN neurons secrete oxytocin, which is stored in the
posterior pituitary gland (Cross & Wakerley, 1977), vaginal or cervical
stimulation releases the oxytocin from the posterior pituitary gland into the
bloodstream—a response known as the Ferguson reflex (Ferguson, 1941)—
and orgasm releases the oxytocin into the bloodstream (Blaicher et al.,
1999; Carmichael et al., 1987,1994; see also McKenna, chap. 4, this volume).
It is of interest that during orgasm, the insular cortex and anterior
cingulate cortices are active, because both of these areas have been reported
to be activated during response to pain (Bornhovd et al., 2002; Casey,
Morrow, Lorenz, & Minoshima, 2001; Ploner, Gross, Timmermann, &
Schnitzler, 2002). This suggests an interesting local interaction between
the pain and pleasure regions of the brain. Further research is needed to
compare directly and in the same individual brain regions that are activated
during pleasure with those activated during pain. The nucleus accumbens
also showed activation during orgasm in the present study. This brain region
has been reported to show fMRI activation during the "rush" induced by
an intravenous injection of nicotine (Stein et al., 1998). Our findings suggest
a role for the nucleus accumbens in mediating orgasmic pleasure in women.
A salient and reliable feature of brain regions activated during orgasm
was activation of the cerebellum. The cerebellum modulates muscle tension
via the gamma efferent system and receives proprioceptive information
(Felten & Jozefowicz, 2003). Because muscle tension can reach peak levels
during orgasm (Masters & Johnson, 1966) and contribute to the sensory
pleasure of orgasm (Komisaruk &. Whipple, 1998, 2000), it is not unlikely
that the cerebellum thereby plays a significant motoric and hedonic role
in orgasm.
While genital self-stimulation is being applied continuously, certain
localized brain regions become activated only when orgasm results from the
stimulation (e.g., the PVN). There are at least two plausible processes that
could account for this: (a) a gradual increase in activity that reaches a
peak at orgasm and consequently shows up only after the activity crosses
a threshold that was arbitrarily set with the fMRI instrumentation, or (b) a
brain region that is specifically related to the unique quality of orgasm that
becomes activated only at orgasm. Further research is required to distinguish
between these two possible processes.

IMPLICATIONS FOR PRACTITIONERS
The physical and psychological trauma of spinal cord injury produce

prolonged and profound disruption in all phases of life and social relation-
ships, among the most troubling of which are bowel and bladder manage-
ment, mobility, and sexuality. In our interviews of women with spinal
cord injury (Komisaruk, Gerdes, &. Whipple, 1997; Whipple, Gerdes, &
Komisaruk, 1996), most of the women lamented the fact that in their
rehabilitation therapy, sexuality received perfunctory discussion, lumped
together with limited sessions on bowel and bladder management. Through
our interviews, a trajectory of adjustment to the occurrence of the spinal
cord injury became evident. We termed the sequence of components of the
trajectory as, initially, cognitive-genital dissociation, followed by a phase of
sexual disenfranchisement, and later, sexual rediscovery (Richards, Tepper,
Whipple, & Komisaruk, 1997). In cognitive-genital dissociation, immedi-
ately postinjury, sexuality was of low priority. As one woman described it,
"I closed up ... I shut down every response ... I shut down being happy
... I shut everything off." There followed a period of relationship disconnec-
tion and disappointment—sexual disenfranchisement. Among 11 women
in committed relationships, 8 believed that their spinal cord injury played
a role in breaking up their relationships. As one woman said, "It wasn't
physically gratifying ... I didn't orgasm like I did before . .. We had finally
gotten to the point of sexual intimacy and it didn't work." Gradually, over
a period of years, a phase of sexual exploration emerged—sexual rediscovery.
Of 13 women interviewed who experienced orgasms prior to their injury,
8 reported experiencing orgasm at latencies ranging from 2 to 15 years
postinjury. One woman said of the need for communication, resourcefulness,
and creativity with a partner, "It kind of forces you to be inventive . .. and
more experimental." Still later, after 8 to 15 years, the women described
becoming more comfortable with their sexuality, developing the ability to
communicate with a partner and to be open about their own sexual needs,
starting to develop a sense of sexual self-esteem.
In our laboratory studies with the women with spinal cord injury,
more than half were surprised that they could feel the vaginal or cervical
stimulation and experience pleasurable sensations including orgasms (see
Komisaruk, Gerdes, & Whipple, 1997, for quotes of their descriptions). The
women commonly said that when they told their physicians that they
experience genital sensations, menstrual discomfort, or orgasms, they were
told that because of the nature of their injury, it is "impossible," that they
are imagining it, or that it is "all in their head." The present findings provide
evidence that, contrary to doctrine, a physical, neurologically functional,
sensory pathway from the vagina and cervix exists via the Vagus nerves,
which can convey sensory activity directly to the brain, bypassing the spinal

cord. As a result, although this pathway may function to a greater or lesser
extent after spinal cord injury, it is possible that even after a complete upper
spinal cord interruption, a woman may experience genital sensation and
sexual pleasure. This possibility should not be summarily dismissed, and it
may even be advisable to explore the possibility of increasing its salience
through rehabilitation.
CONCLUSIONS
The above findings lead us to three major conclusions: First, in women,

the Vagus nerves provide a genital (cervical) sensory pathway that com'
pletely bypasses the spinal cord, projecting directly to the brain, and conse-
quently can provide genital sensation despite complete spinal cord interrup-
tion at any level. This should be heeded by health care practitioners to
avoid informing women, after such injury, that genital sensation is no
longer possible. Instead, individual testing is indicated before making such
categorical assumptions. Second, the genital sensory activity conveyed by
the Vagus nerves, to the exclusion of the genitospinal nerves, is evidently
adequate to induce orgasm in some women. This provides a minimal and
thereby "simplified" informational neural input that could facilitate elucida-
tion of the neural mechanisms underlying orgasm, which is an intriguing
and compelling neurophysiological process. Third, specific brain regions
appear to be uniquely activated at orgasm. (For further details and discussion,
see Komisaruk et al., 2004.)
REFERENCES
American Spinal Injury Association. (1992). Standards for neurological and functional
classification of spinal cord injury—Revised. Chicago: Author.
Balkin, T. J., Braun, A. R., Wesensten, N. J., Jeffries, K., Varga, M., Baldwin, P.,
et al. (2002). The process of awakening: A PET study of regional brain activity
patterns mediating the re-establishment of alertness and consciousness. Brain,
125, 2308-2319.
Berard, E. J. J. (1989). The sexuality of spinal cord injured women: Physiology and
pathophysiology—A review. Paraplegia, 27, 99-112.
Berkley, K. J., Hotta, H., Robbins, A., & Sato, Y. (1990). Functional properties of
afferent fibers supplying reproductive and other pelvic organs in pelvic nerve
of female rats. Journal ofNeurophysiology, 63, 256-272.
Bianca, R., Sansone, G., Cueva-Rolon, R., Gomez, L. E., Ganduglia-Pirovano, M.,
Beyer, C., et al. (1994). Evidence that the Vagus nerve mediates a response

to vaginocervical stimulation after spinal cord transaction in the rat. Society
for Neuroscience Abstracts, 20, 961.
Blaicher, W., Gruber, D., Bieglmayer, C., Blaicher, A. M., Knogler, W., & Huber,
J. C. (1999). The role of oxytocin in relation to female sexual arousal. Gyneco-
logic and Obstetric Investigation, 47, 125-126.
Bonica, J. J. (1967). Principles and practices of obstetric analgesia and anesthesia. Phila-
delphia: Davis.
Bomhovd, K., Quante, M., Glauche, V., Bromm, B., Weiller, C., & Buchel, C.
(2002). Painful stimuli evoke different stimulus-response functions in the
amygdala, prefrontal, insula and somatosensory cortex: A single-trial fMRI
study. American Journal of Gastroenterology, 97, 654-661.
Carmichael, M. S., Humbert, R., Dixen, J., Palmisano, G., Greenleaf, W., & David-
Carmichael, M. S., Warburton, V. L., Dixen, J., & Davidson, J. M. (1994). Relation-
ships among cardiovascular, muscular, and oxytocin responses during human
sexual activity. Archives of Sexual Behavior 23, 59-79.
Casey, K. L., Morrow, T. J., Lorenz, J., & Minoshima, S. (2001). Temporal and
spatial dynamics of human forebrain activity during heat pain: Analysis by
positron emission tomography. Journal of Neurophysiology, 85, 951-959.
Cole, T. (1975). Sexuality and physical disabilities. Archives of Sexual Behavior, 4,
389-403.
Collins, J. J., Lin, C. E., Berthoud, H. R., & Papka, R. E. (1999). Vagal afferents
from the uterus and cervix provide direct connections to the brainstem. Cell
and Tissue Research, 295, 43-54.
Cross, B. A., & Wakerley, J. B. (1977). The neurohypophysis. International Review
of Physiology, 16, 1-34.
Cueva-Rolon, R., Sansone, G., Bianca, R., Gomez, L. E., Beyer, C., Whipple, C.,
et al. (1994). Evidence that the Vagus nerve mediates some effects of vaginocer-
vical stimulation after genital deafferentation in the rat. Society for Neuroscience
Abstracts, 20, 961.
Cueva-Rolon, R., Sansone, G., Bianca, R., Gomez, L. E., Beyer, C., Whipple, B.,
& Komisaruk, B. R. (199.6). Vagotomy blocks responses to vaginocervical
stimulation after genitospinal neurectomy in rats. Physiology and Behavior,
60, 19-24.
Cunningham, S. T., Steinman, J. L., Whipple, B., Mayer, A. D., & Komisaruk,
B. R. (1991). Differential roles of hypogastric and pelvic nerves in analgesic
and motoric effects of vaginocervical stimulation in rats. Brain Research,
559, 337-343.
Ding, Y. Q., Shi, J., Wang, D. S., Xu, J. Q., Li, J. L, & Ju, G. (1999). Primary
afferent fibers of the pelvic nerve terminate in the gracile nucleus of the rat.
Neuroscience Letters, 272, 211-214.

Erskine, M. S., & Hanrahan, S. B. (1997). Effects of paced mating on c-fos gene
expression in the female rat brain, journal ofNeuroendocrinology, 9, 903-912.
Felten, D. L., & Jozefowicz, R. F. (2003). Netter's atlas of human neuroscience. Teter-
boro, NJ: Icon Learning Systems.
Ferguson, J. K. W. (1941). A study of the motility of the intact uterus at term.
Surgical Gynecology and Obstetrics, 73, 359-366.
Gomora, P., Beyer, C., Gonzalez-Mariscal, G., & Komisaruk, B. R. (1994). Momen-
tary analgesia produced by copulation in female rats. Brain Research, 656,
52-58.
Hamann, S. B., Herman, R. A., Nolan, C. L., & Wallen, K (2002). Sex differences
in neural response to visual sexual stimuli revealed by fMRl (Program No. 620.14):
Abstract viewer/itinerary planner [CD-ROM]. Washington, DC: Society for
Neuroscience.
Holstege, G., Georgiadis, J. R., Paans, A. M. J., Meiners, L. C., van der Graaf,
F. H. C. E., & Reinders, A. A. T. S. (2003). Brain activation during human
male ejaculation. Journal of Neuroscience, 23, 9185-9193.
Hubscher, C. H., & Berkley, K. J. (1994). Responses of neurons in caudal solitary
nucleus of female rats to stimulation of vagina, cervix, uterine horn and colon.
Hubscher, C. H., &. Berkley, K. J. (1995). Spinal and vagal influences on the
responses of rat solitary nucleus neurons to stimulation of uterus, cervix and
vagina. Brain Research, 702, 251-254.
Kettl, P., Zarefoss, S., Jacoby, K., Garman, C., Hulse, C., Rowley, F., et al. (1991).
Female sexuality after spinal cord injury. Sexuality and Disability, 9, 287-295.
Kirchner, A., Birklein, F., Stefan, H., & Handwerker, H. O. (2000). Left Vagus nerve
stimulation suppresses experimentally induced pain. Neurology, 55, 167-171.
Komisaruk, B. R., Adler, N. T., & Hutchison, J. (1972, December 22). Genital
sensory field: Enlargement by estrogen treatment in female rats. Science,
178, 1295-1299.
Komisaruk, B. R., Bianca, R., Sansone, G., Gomez, L. E., Cueva-Rolon, R., Beyer,
C., & Whipple, B. (1996) Brain-mediated responses to vaginocervical stimula-
tion in spinal cord-transected rats: Role of the Vagus nerves. Brain Research,
708, 128-134.
Komisaruk, B. R., Cueva-Rolon, R., Gomez, L., Ganduglia-Pirovano, M., Sansone,
G., & Bianca, R. (1995). Vagal afferent electrical stimulation produces pupil
dilatation in the rat. Society for Neuroscience Abstracts, 21, 1156.
Komisaruk, B. R., Gerdes, C. A., & Whipple, B. (1997). "Complete" spinal cord
injury does not block perceptual responses to genital self-stimulation in women.
Komisaruk, B. R., Mosier, K. M., Criminale, C., Liu, W.-C., Zaborszky, L., Whipple,
B., & Kalnin, A. J. (2002). Functional localization of brainstem and cervical
spinal cord nuclei in humans with fMRI. American journal of Neuroradiology,
23, 609-607.

Komisaruk, B. R., & Whipple, B. (1984). Evidence that vaginal self-stimulation in
women suppresses experimentally-induced finger pain. Society for Neurosdence
Abstracts, 10, 675.
Komisaruk, B. R., & Whipple, B. (1994). Complete spinal cord injury does not
block perceptual responses to vaginal or cervical self-stimulation in women.
Society for Neurosdence Abstracts, 20, 961.
Komisaruk, B. R., & Whipple, B. (1995). The suppression of pain by genital stimula-
tion in females. Annual Review of Sex Research, 6, 151-186
Komisaruk, B. R., & Whipple, B. (1998). Love as sensory stimulation: Physiological
consequences of its deprivation and expression. Psychoneuroendocrinology,
23, 927-944.
Komisaruk, B. R., & Whipple, B. (2000). How does vaginal stimulation produce plea-
sure, pain and analgesia? In R. B. Fillingim (Ed.), Pain research and management:
Vol. 17. Sex, gender and pain (pp. 109-134). Seattle, WA: IASP Press.
Komisaruk, B. R., Whipple, B., Crawford, A., Grimes, S., Kalnin, A. J., Mosier, K.,
et al. (2002). Brain activity (fMRl and PET) during orgasm in women in response
to vaginocervical self-stimulation (Program No. 841.17): Abstract viewer/itinerary
planner [CD-ROM]. Washington, DC: Society for Neuroscience.
Komisaruk, B. R., Whipple, B., Crawford, A., Grimes, S., Liu, W-C., Kalnin, A.,
& Mosier, K. (2004). Brain activation during vaginocervical self-stimulation
and orgasm in women with complete spinal cord injury: fMRI evidence of
mediation by the Vagus nerves. Brain Research, 1024, 77-88.
Komisaruk, B. R., Whipple, B., Gerdes, C., Harkness, B., & Keyes, J. W., Jr. (1997).
Brainstem responses to cervical self-stimulation: preliminary PET-scan analysis.
Society for Neurosdence Abstracts, 23, 1001.
Komisaruk, B., Whipple, B., Gerdes, C. A., Sansone, G., Bianca, R., Cueva-Rolon,
R., et al. (1996, June). Further evidence that the Vagus nerve conveys genital
sensory activity directly to the brain, bypassing the spinal cord. In Proceedings of
the International Behavioral Neuroscience Society. San Antonio, TX: International
Behavioral Neuroscience Society.
Kow, L. M., & Pfaff, D. W. (1973-74). Effects of estrogen treatment on the size of
receptive field and response threshold of pudendal nerve in the female rat.
Neuroendocrinolog}!, 13, 299-313.
Masters, W. H., & Johnson, V. E. (1966). Human sexual response. Boston: Little,
Brown.
Maixner, W., & Randich, A. (1984). Role of the right vagal nerve trunk in
antinociception. Brain Research, 298, 374-377.
Ness,T. J., Randich, A., Fillingim, R., Faught, R. E., &Backensto, E. M. (2001). Left
vagus nerve stimulation suppresses experimentally induced pain. Neurology, 56,
985-986.
Ortega-Villalobos, M., Garcia-Bazan, M., Solano-Flores, L. P., Ninomiya-Alarcon,
J.G., Guevara-Guzman, R., & Wayner, M. J. (1990). Vagus nerve afferent
and efferent innervation of the rat uterus: An electrophysiological and HRP
study. Brain Research Bulletin, 25, 365-371.

Peters, L. G, Kristal, M. B., & Komisaruk, B. R. (1987). Sensory innervation of the
external and internal genitalia of the female rat. Brain Research, 408, 199-204-
Pfaus, J. G., Damsma, G., Wenkstern, D., & Fibiger, H. C. (1995). Sexual activity
increases dopamine transmission in the nucleus accumbens and striatum of
female rats. Brain Research, 693, 21-30.
Pfaus, J. G., &Heeb, M. M. (1997). Implications of immediate-early gene induction
in the brain following sexual stimulation of female and male rodents. Brain
Research Bulletin, 44, 397-407.
Ploner, M., Gross,]., Timmermann, L., & Schnitzler, A. (2002). Cortical representa-
tion of first and second pain sensation in humans. Proceedings of the National
Academy of Sciences USA, 99, 12444-12448.
Randich, A., & Gebhart, G. F. (1992). Vagal afferent modulation of nociception.
Brain Research Reviews, 17, 77-99.
Richards, E., Tepper, M., Whipple, B., & Komisaruk, B. R. (1997). Women with
complete spinal cord injury: A phenomenological study of sexuality and rela-
tionship experiences. Sexuality and Disability, 15, 271-283.
Rowe, D. W., & Erskine, M. S. (1993). c-Fos proto-oncogene activity induced by
mating in the preoptic area, hypothalamus and amygdala in the female rat:
Role of afferent input via the pelvic nerve. Brain Research, 621, 25-34.
Sansone, G. R., Gerdes, C. A., Steinman, J. L., Winslow, J. T., Ottenweller, J. E.,
Komisaruk, B. R., & Insel, R. T. (2002). Vaginocervical stimulation releases
oxytocin within the spinal cord in rats. Neuroendocrinology, 75, 306-315.
Sipski, M. L., & Alexander, C. J. (1995). Spinal cord injury and female sexuality.
Annual Review of Sex Research, 6, 224-244.
Sipski, M. L., Alexander, C. J., & Rosen, R. C. (1995). Orgasm in women with
spinal cord injuries: A laboratory-based assessment. Archives of Physical Medicine
and Rehabilitation, 76, 1097-1102.
Stein, E. A., Pankiewicz, ]., Harsch, H. H., Cho, J. K., Fuller, S. A., Hoffmann,
R. G., et al. (1998). Nicotine-induced limbic cortical activation in the human
brain: A functional MRI study. American Journal of Psychiatry, 155, 1009-1015.
Tetel, M. J., Getzinger, M. J., & Blaustein, J. D. (1993). Fos expression in the rat
brain following vaginal-cervical stimulation by mating and manual probing.
Tiihonen, J., Kuikka, J., Kupila, J., Partanen, K., Vainio, P., Airaksinen, J., et al.
(1994). Increase in cerebral blood flow of right prefrontal cortex in man during
orgasm. Neuroscience Letters, 170, 241-243.
Toniolo, M. V., Whipple, B. H., & Komisaruk, B. R. (1987). Spontaneous maternal
analgesia during birth in rats. In Proceedings of the N1H Centennial MBRS-
MARC Symposium (p. 100). Bethesda, MD: National Institutes of Health.
Travers, S. P., & Norgren, R. (1995). Organization of orosensory responses in the
nucleus of the solitary tract of rat. Journal of Neurophysiology, 73, 2144-2162.
Veening,]. G.,&Coolen, L. M. (1998). Neural activation following sexual behavior
in the male and female rat brain. Behavioral Brain Research, 92, 181-193.
J 44 KOMISARUK AND WHIPPLE

Wersinger, S. R., Baum, M. J., & Erskine, M. S. (1993). Mating-induced FOS-like
immunoreactivity in the rat forebrain: A sex comparison and a dimorphic
effect of pelvic nerve transection. Journal of Neuroendocrinology, 5, 557-568.
Whipple, B. (1990). Female sexuality. In J. Leyson (Ed.), Sexual rehabilitation of the
spinal cord injured patient (pp 19-38). Clifton, NJ: Humana Press.
Whipple, B., Gerdes, C., & Komisaruk, B. R. (1996). Sexual response to self-
stimulation in women with complete spinal cord injury. Journal of Sex Research,
33, 231-240.
Whipple, B., & Komisaruk, B. R. (1985). Elevation of pain threshold by vaginal
stimulation in women. Pain, 21, 357-367.
Whipple, B., & Komisaruk, B. R. (1988). Analgesia produced in women by genital
self-stimulation. Journal of Sex Research, 24, 130-140.
Whipple, B., & Komisaruk, B. R. (2002). Brain (PET) responses to vaginal-cervical
self-stimulation in women with complete spinal cord injury: Preliminary find-
ings. Journal of Sex and Marital Therapy, 28, 79-86.
Wildt, L., Kissler, S., Licht, P., & Becker, W. (1998). Sperm transport in the human
female genital tract and its modulation by oxytocin as assessed by hysterosal-
pingoscintigraphy, hysterotonography, electrohysterography and Doppler son-
ography. Human Reproduction Update, 4, 655-666.

NEUROANATOMICAL AND
NEUROTRANSMITTER
DYSFUNCTION AND COMPULSIVE
SEXUAL BEHAVIOR
ELI COLEMAN
Individuals with compulsive sexual behavior (CSB) are often unable

to control their sexual behavior, may act out impulsively, and/or are often
plagued by intrusive obsessive thoughts and driven behaviors. They often
perceive their behavior as excessive and experience serious consequences
(Coleman, Raymond, & McBean, 2003). It is unfortunate that clinical
sexologists appear unable to reach consensus on what to call or how to treat
such sexual behavior. Terms have been used to describe this phenomenon,
including hypersexuality, erotomania, nymphomania, satyriasis, and, most re-
cently, sexual addiction and compulsive sexual behavior. The terminology has
often implied different values, attitudes, and theoretical orientations, and the
debate continues regarding classification, causes, and treatment (Coleman,
1990, 1991, 1992). Despite the lack of consensus of terminology, there is
consensus that just as there can be problems with hyposexuality, there are
individuals who experience hypersexuality (Coleman, 2003).
In my work and throughout this chapter, I use the term compulsive
sexual behavior (CSB) to describe this syndrome. I use this term to describe
147
the clinical phenomenon but leave open the possibility of multiple etiol-
ogies and treatments. Some of the behavioral problems appear to be problems
of impulse control rather than driven by obsessive-compulsive mechaynisms.
These behaviors are not always ego-dystonic, as in classic obsessive-
compulsive disorder (Raymond, Coleman, Benefield, & Miner, 2003). Other
times, it seems to be a function of a generalized hypersexual drive, or it
seems to function as a dysregulated pleasure-seeking behavior (Coleman et
al., 2003).
THE NATURE OF COMPULSIVE SEXUAL BEHAVIOR
Compulsive sexual behaviors can be divided into two main types:

paraphilic and nonparaphilic (Coleman, 1991). Paraphilic CSB involves
unconventional sexual activities that often interfere in social, interpersonal,
and occupational functioning. In the recent Diagnostic and Statistical Manual
of Mental Disorders (4th ed., text revision; DSM-IV-TR), paraphilias are
defined as "recurrent, intense sexually arousing fantasies, sexual urges, or be-
haviors generally involving (1) nonhuman objects, (2) the suffering or humili-
ation of oneself or one's partner, or (3) children or other non-consenting
persons" (American Psychiatric Association, 2000, p. 566). The definition
goes on to explain, "The behavior, sexual urges, or fantasies cause clinically
significant distress in social, occupational, or other important areas of
functioning" (p. 566).
Nonparaphilic CSB involves conventional behaviors. The DSM-IV-
TR describes one example under the heading of "Sexual Disorder Not
Otherwise Specified" as "Distress about a pattern of repeated sexual relation-
ships involving a succession of lovers who are experienced by the individual
only as things to be used" (American Psychiatric Association, 2000, p. 582).
However, there are a number of other types of nonparaphilic CSB that
have been identified (Coleman, 1992).
In the past, my colleagues and I have used a slight variation of the
paraphilia diagnostic criteria (Coleman et al., 2003):
A. Intense, sexually arousing behaviors, sexual urges, or fantasies that
involve one of the following:
(1) Compulsive cruising and multiple sexual partners
(2) Compulsive fixation on an unattainable partner
(3) Compulsive autoeroticism
(4) Compulsive use of the Internet for sexual purposes
(5) Compulsive use of erotica
(6) Compulsive multiple love relationships
(7) Compulsive sexuality in a relationship
148 ELI COLEMAN

B. The fantasies, sexual urges, or behaviors cause clinically significant
distress or impairment in social, occupational, or other important
areas of functioning.
C. Not because of another medical condition, substance use disorder,
or attributable to another Axis I or II disorder, developmental
disorder. Must take into account norms of gender, sexual orienta-
tion, and sociocultural groups.
D. Duration of at least 6 months.
There are myriad hypothesized causes for CSB. However, the focus of
this chapter is on neuroanatomical and neurotransmitter dysregulation and
dysfunction that have been implicated in causing at least some cases of
CSB. Studies are under way exploring hypothesized neuroanatomic and
neurophysiological abnormalities through functional neuroimaging. It is
hoped that these studies will lead to improved pharmacologic treatment
and will be a helpful adjunct for the necessary psychotherapeutic treatment
(Coleman, 1995; Coleman, Cesnik, Moore, & Dwyer, 1992).
NEUROANATOMICAL ABNORMALITIES
It has been hypothesized that sexual abnormalities may have their

origin in the centers and pathways in the brain that are responsible for
sexual arousal and mating behavior. The main part of the brain that has
been implicated is the limbic system consisting of the amygdala, the hippo-
campus, and the hypothalamus. This is also known as the paleomammalian
cortex. In addition to sexual functions, the limbic system is also responsible
for other elemental functions of individual and species survival, including
fight-or-flight responses. The hippocampus and amygdala are covered by the
temporal lobe of the neomammalian cortex. The frontal lobe acts as an
executive function over the rest of the brain.
Disturbed communication pathways between the frontal and temporal
lobe have been implicated in many of the neurological disturbances that
may be responsible for CSB. Also, the close proximity of sexual arousal and
fight-or-flight responses in the brain is implicated in disorders of sexual
violence (Money, 1990). There have been a number of case reports of
individuals who developed pedophilic or hypersexual behaviors after some
type of cerebral event, such as stroke, traumatic injury, or development of
diseases that affect cerebral structure. In addition, disinhibited sexual activity
and paraphilias have been reported following lesions in the frontal lobe,
hypothalamus, and septum (Frohman, Frohman, & Moreault, 2002; Miller,
Cummings, Mclntyre, Ebers, & Grode, 1986).
NEUROANATOMICAL AND NEUROTRANSMITTER DYSFUNCTION 149

Most of the brain abnormalities have been found in paraphilic CSB.
Berlin (1988) and Langevin (1990) have provided good reviews of this
literature. They have cautioned, however, that as a group paraphilics do not
differ from control groups on the basis of brain abnormalities. However,
medical technology is advancing so fast that one is now able to see and
understand brain mechanisms and neurotransmitter pathways in ways that
previously were not possible. The use of computer tomography imaging
(CT), magnetic resonance imaging (MRI), functional magnetic resonance
imaging (fMRI), and positron emission tomography (PET) have made revo-
lutionary inroads in the understanding of psychiatric disorders and the
development of pharmacological treatments. The search for neuroanatomi'
cal and neurophysiological correlates of sexual disorders will obviously in-
crease in intensity in the near future. It is naive to think that any simple
brain mechanism or neurotransmitter will explain the complexity of human
sexual expression or disorders. However, there should be great optimism
of further unlocking the mysteries of the brain, neurochemistry, and its
relationship to sexual behavior.
Frontal Lobe Abnormalities
Frontal lobe dysfunction can lead to disinhibition of sexual behavior

and hypersexual behavior or CSB. Based on a review of the literature, Miller
et al. (1986) concluded that frontal lobe abnormalities were more associated
with hypersexuality and that the temporal lobe dysfunctions were more
related to pedophilic sexual interests.
The frontal lobes are responsible for "executive functioning" such as
response inhibition, planning, and verbal mediation of behavior. Lesions
of frontal brain have been shown to produce impulse control problems,
including hypersexual behavior (Damasio, Tranel, & Damasio, 1990; Elliot
& Biever, 1996).
Studies are under way to examine structural and functional MRI scans
in an attempt to understand what portions of frontal lobe as well as other
parts of the brain are functioning abnormally in individuals with CSB. It
is hoped that these studies will further unlock the mysteries of the potential
neuroanatomical and neurophysiological factors involved in CSB and lead
to improved treatment.
Temporal Lobe Abnormalities
There has been a great deal of focus on the hypothesized involvement

of the temporal lobe in CSB. Temporal lobe abnormalities, which have
been associated with hypersexuality, also may be involved in development
of various paraphilias such as fetishes and pedophilia. John Money has noted
150 ELICOLEMAN
that, in some case reports, comorbidity exists between paraphilias with
temporal lobe lesion(s) and seizures. In these patients, when the lesion can
be corrected through neurosurgery, the paraphilia disappears (Money &
Lamarz, 1990). In addition, temporal lobe epilepsy has been associated with
states that are a common feature of CSB (Mesulam, 1981). For example,
Money and Lamarz (1990) described the fuguelike state, which is an altered
state of consciousness and which is activated when the paraphilia engage
in their paraphilic activity. They noted that there may be a correlation
with some temporal lobe seizurelike activity. In some cases, disturbances of
cortical electrical activity in the regions of the brain related to the limbic
system may provide explanation for obsessive thoughts, or fuguelike states
associated with CSB, or the compulsive behaviors themselves.
Further evidence of temporal lobe involvement comes from studies of
stroke victims. Although hyposexuality is a common problem in stroke pa-
tients, some clinicians have noted hypersexuality and unusual sexual behavior
among patients after a stroke (Monga, Monga, Raina, & Hardjasudarma,
1986). In the patients who showed hypersexuality, CT scans indicated
temporal lobe lesions, and all had a history of poststroke seizure activity.'
Faulty functioning could be triggered by the growth of a tumor or from
an open or closed head injury. This can result in seizurelike activity of the
nonconvulsive type. An example of this would be the Kluver-Bucy syndrome,
a disorder in which a temporal lobe lesion leads to hypersexuality. This was
first noted in animals (Kluver & Bucy, 1939) and then in humans (Goscinski,
Kwiatkowski, Polak, Orlowiejska, & Partyk, 1997; Nakada, Lee, Kwee, &.
Lerner, 1984; Pearce & Miller, 1973). "Hypersexuality" and alterations in
sexual orientation have been noted in a number of patients following brain
injury (Elliott & Biever, 1996; Huws, Shubsachs, & Taylor, 1991; Mendez,
Chow, Ringman, Twitchell, & Hinkin, 2000; Miller et al., 1986; Ortego,
Miller, Itabashi, & Cummings, 1993).
Researchers have also suggested, on the basis of case studies, that
pedophilic interests are associated with abnormalities in the temporal lobe or
midbrain adjacent to the hypothalamus (Kolarsky, Madlafousek, & Novotna,
1978; Miller et al., 1986; Ortego et al., 1993). Others have concluded that
these temporal lobe disturbances actually result in hypersexuality, and this
hypersexuality may unmask a previously hidden orientation toward children
(Mendez et al., 2000). It should be noted that these findings are based on
very few case studies. And, the majority of individuals with temporal lobe
epilepsy or temporal lobe damage (e.g., stroke) or those with temporal
lobectomy experience hyposexual desire, but a small percentage of patients
experience hypersexuality (Blumer, 1970; Blumer & Walker, 1967; Monga
et al., 1986). The reasons for this are unclear.
Although birth defects, head traumas, strokes, or brain surgeries can
alter temporal lobe functioning, one can also speculate about the impact
NEUROANATOM1CAL AND NEVROTRANSM1TTER DYSFUNCTION 151

of physical or emotional abuse. Individuals with CSB have reported dis-
proportionately high levels of physical and emotional abuse as children
(Coleman, 1991). This is true of many psychiatric disorders. Although most
patients with CSB do not have temporal lobe epilepsy or known neurological
disorders, one speculates what effect physical or emotional abuse or specifi-
cally head injuries associated with physical abuse have had on their develop-
ing brains (Coleman, 1991).
Some of my patients have suspected temporal lobe disturbances, but
neurological testing had been inconclusive. However, this does not rule out
that neurological abnormalities exist in these patients. In one case of a
pedophile, neurological findings were negative. His inability to concentrate,
tendency to lose track of his conversation, cognitive distortions, hyper-
reactivity, and rapid shifts in personality all pointed to some neurological
disturbance. Given this speculation and the fact that he was not improving
with psychotherapy, our clinical team decided to give him a trial of a
mood stabilizer (carbamazapine). He reported improvement in his cognitive
functioning, hyperreactivity, and interpersonal communication. I could ob-
serve these behavioral changes, and they were also noted by his therapy
group members. In questioning his sister on whether she had noted any
changes since her brother began the medication, she gave me an immediate
example, "I feel like I just had my first real conversation with him while
we were waiting in the reception area." There was no change in his sexual
arousal patterns, but his improved cognitive ability and interpersonal skills
seemed to be having an effect on his overall self-esteem and control of his
pedophilic interests. Therapy was also able to progress at a more rapid pace,
and he eventually successfully completed treatment. One can only speculate
on the temporal lobe involvement in this case; however, there may have
been some involvement as part of the constellation of factors that may have
contributed, maintained, or made rehabilitation difficult. Although this is
just a case example, I have seen a number of similar cases with positive results.
NEUROPHYSIOCHEMICAL ABNORMALITIES
Chemical reactions in the nervous system, in the form of hormones

and other neurochemicals, have significant effects on behavior. In this
section I discuss some ways that abnormalities in these processes might
affect CSB.
Testosterone
Studies that have tried to correlate testosterone and CSB focused on

sexual offenders and have been fraught with methodological problems and
152 ELI COLEMAN

contradictory results. Not all sexual offenders necessarily meet diagnostic
criteria for paraphilic disorder. In addition, basic understanding of endocri-
nology information is often ignored in interpreting the findings of many of
these studies. For example, clinically relevant hormonal mechanisms are
rarely reflected in total plasma testosterone levels. Measurement of the
unbound plasma testosterone is rarely measured, and this is the biologically
active portion of the total. The range of normal plasma testosterone levels
is large. The clinically relevant information is probably more reflected in
receptor sites; however, there have been no easy means developed to measure
hormone receptivity. Thus, most studies continue to measure total plasma
testosterone without careful interpretation of this information.
In one study, plasma testosterone levels in 52 male rapists and 12 male
child molesters were measured (Rada, Laws, & Kellner, 1976). The ranges
of the rapists and the child molesters were within normal limits. However,
the rapists whose crimes were judged to be most violent had significantly
higher plasma testosterone levels than other rapists and child molesters. Rada
et al. were careful to point out the limitations in interpreting these results.
Researchers have noted that external factors could account for these
variations in plasma testosterone levels (Rada, Kellner, & Winslow, 1976).
For example, the stresses of having been arrested or incarcerated could alter
and influence plasma testosterone. Changes could also be due to chronic
ingestion of alcohol, which has been noted to reduce plasma testosterone
levels (Mendelson & Mello, 1974). The effects of stress and anxiety must
be taken into account when interpreting data on plasma testosterone levels.
Even methods of gathering plasma testosterone levels (time and method)
can create spurious differences. It may be that the precision of assay tech-
niques was still too crude to note any abnormalities.
However, in assessing the role of sexual hormones on sexual behavior
in 1977, John Bancroft was not hopeful about science providing some clear
answers in the near future. He suggested that "those psychiatrists looking
for simple biological explanations of human behavior would be advised to
search elsewhere" (Bancroft, 1977, p. 555). Researchers have essentially
followed this advice in terms of looking for abnormalities of testosterone
studies. Since the initial inconclusive studies, this line of research was
abandoned. However, with better assay techniques and more precision as
to type of offender, it seems that it would be useful to conduct further studies
of plasma testosterone levels, recognizing the probable complexity of factors
associated with offending behavior.
Although studies have not been conclusive about abnormalities of
testosterone levels, the efficacy of antiandrogen treatment for sex offenders
and individuals with CSB has been fairly well documented (Bradford,
2000). It is assumed that lowering testosterone levels reduces libido and
gives greater control to individuals who feel "driven" by their paraphilic or
NEUROANATOMIC AL AND NEUROTRANSM1TTER DYSFUNCTION 153

nonparaphilic urges. However, because lowering testosterone has a cascading
effect on other neurotransmitters, there may be a more complex explanation.
Because I have always felt that CSB is driven more by anxiety reduction
mechanisms than by sexual drive, I have been more interested in the neuro-
physiochemical processes involved in stress and the pharmacological treat-
ments that could alleviate a person's maladaptive stress response.
Autonomic Reactivity and Neurotransmitter Dysregulation
Because many individuals with CSB have experienced abuse in child-

hood, it is interesting to speculate what effect this might have had on their
neurophysiochemical functioning. There are no data on individuals with
CSB in this regard, but there is a body of research on individuals with
posttraumatic stress disorder (PTSD) that might suggest similarities. Studies
in animals and humans have focused on the specific brain areas and circuits
involved in anxiety and fear, which are important for understanding anxiety
disorders such as PTSD. The fear response is coordinated by a small structure
deep inside the brain, called the amygdala. It has been suggested that the
different anxiety disorders are associated with abnormal activation of the
amygdala (LeDoux, 1998).
People with PTSD tend to have abnormal levels of key hormones
involved in response to stress (Yehuda, 1998). Individuals who have PTSD
have been shown to display increased autonomic reactivity to auditory
stimuli in laboratory conditions (Kolb & Mutalipassi, 1982). van der Kolk
(1983) described how patients with PTSD have a poor tolerance for arousal,
and this condition interferes with cognitive responses to stressful stimuli.
He suggested that these patients experience a conditioned response to emo-
tional and sensory stimulation and react with psychomotor discharge or
by psychological withdrawal. Their overt behavior may be regulated by
conditioned autonomic reactivity. Because many individuals with CSB have
been traumatized in childhood, this could result in increases in autonomic
reactivity as well. Behaviors (including CSB) may be viewed as an inappro-
priate and exaggerated response to a perceived threat.
These neurophysiological abnormalities may possibly have a genetic
basis, which gives the individual an inborn predisposition for the develop-
ment of these neurophysiological abnormalities causing increased autonomic
reactivity. Parents may pass on this genetic trait to their children. This may
explain why some individuals who experience trauma develop maladaptive
stress responses whereas others have more resilience. For the more vulnerable
or less resilient, events or traumas that create hormonal abnormalities at
critical events of the development of the brain may later influence psychosex-
ual development and functioning.
154 ELICOLEMAN
This line of research on PTSD has implications for understanding
some of the behavior of persons with PTSD and therapy. Psychotherapy
can trigger exaggerated emotional responses, over which the individual has
little or no control. The overreactivity can be easily misinterpreted by the
therapist. The client may be seen as unmanageable, resistant, or avoidant.
van der Kolk (1984) indicated the importance of using psychopharmacologic
agents to focus on these patients' hyperreactivity, which might include
anxiety, impulsivity, anger outbursts, intrusive nightmares or flashbacks,
insomnia, depression, and anhedonia.
van der Kolk (1984) provided another possible explanation for the
repetitive nature of CSB. There are autonomic nervous system explanations
that provide an alternative to the common psychodynamic view of etiology
of CSB. The psychodynamic view postulated that the individual was in
some ways trying to resolve conflicts created in childhood through coping
mechanisms, attempts at mastery, avoidance of anxiety, or to "triumph over
the trauma" (Stoller, 1975). Evidence suggests that as a result of trauma,
there is altered autonomic nervous system function (Kolb, Burris, & Griffiths,
1984). It has been hypothesized that the trauma produces effects similar to
those of inescapable shock. The effects of inescapable shock on the central
neurotransmitter systems have been studied extensively. In animal studies,
it is known that exposure to inescapable shock increases norepinephrine
turnover, which results in depleted brain norepinephrine; increases plasma
catecholamine levels; decreases brain dopamine and serotonin; and increases
acetylcholine (van der Kolk, Greenberg, Boyd, & Krystal, 1985). Further
exposure to stress (even minor) will evoke a maladaptive stress response,
van der Kolk (1988) noted that child abuse is correlated with neurochemical
alterations. It may be that such fearful experiences are recorded in one's
nervous system. A conditioned fearful response may be then triggered neuro-
physiologically by any fearful stimulus (see Figure 6.1).
Dysregulation of serotonin, dopamine, and norepinephrine could result
in an abnormal stress response but could be directly implicated in heightened
or inhibited sexual arousal. The brain's neurotransmitter substances, dopa-
mine and serotonin, seem to have particular excitatory and inhibitory func-
tions on sexual drive. Though their exact role is yet to be discovered, it is
generally known that dopamine activates erotosexual interest and serotonin
acts as an inhibitor (Bitran & Hull, 1987; Gessa & Tagliamonte, 1974).
Most research has focused on the roles of serotonin and dopamine.
Dysregulaton of Norepinephrine
Norepinephrine is a neurotransmitter released during stress. One of

its functions is to activate the hippocampus, the brain structure involved

MechaniSfn Maladaptive Mechanism
Severe or Chronic
increase in synthesis
Low fncrease in synthesis of norepinephrine,
of norepinephrine, dooamine and serotonin
dopamine and serotonin
Depletion of norephinephrtne,
dopamine and serotonin
Stabilization
Figure 6.1. Adaptive and maladaptive neurotransmitter response to stress.
with organizing and storing information for long-term memory. Under the
extreme stress of trauma, norepinephrine may act longer or more intensely
on the hippocampus, leading to the formation of abnormally strong memories
that are then experienced as flashbacks or intrusions. It is also interesting
to note that individuals with PTSD have shown atrophy or deterioration
of the hippocampus (R. J. Davidson, Jackson, & Kalin, 2000). This may
explain the development of PTSD symptoms in individuals.
Dysregulation of Serotonin and Dopamine
There is an extensive literature that explains the role of serotonin on

sexual arousal and function (Bancila et al, 1999; Marson & McKenna,
1992; Steinbusch, 1981). Animal studies have shown that decreased seroto-
nin levels will enhance sexual arousal and function, whereas increased levels
will inhibit sexual function (Marson & McKenna, 1992). In humans, the
effect on sexual functioning can be clearly seen in the administration of
selective serotonin reuptake inhibitors (SSRIs). These medications were
developed for the treatment of depression and were designed to increase
serotonin levels. The most common side effect of the SSRIs is the inhibition
of ejaculation and orgasm and the decrease in sexual desire (Lane, 1997;
Modell, Katholi, Modell, & DePalma, 1997). Although these drugs appar-
ently affect serotonin levels, their pharmacology is vastly more complex,
156 ELI COLEMAN

and it is assumed that other neurotransmitter systems are being directly or
indirectly affected. It is known, for example, that increasing serotonin will
have cascading effects on other neurotransmitter systems. In terms of CSB,
serotonergic agents have been found to be effective in treating this clinical
syndrome (Coleman, 1991; Federoff, 1993; Kafka & Coleman, 1991).
Dopamine also plays an important function in sexual arousal. Numerous
pharmacological studies in animals and humans support this conclusion. In
general, dopaminergic agonists facilitate several aspects of sexual function,
including erection, ejaculation, female sexual arousal, and sexual motivation.
In addition, dopaminergic agents used for the treatment of Parkinsonism
sometimes induce increases in sexual desire. In anecdotal reports, cocaine
and amphetamine, which increase dopamine, have been shown to have
aphrodisiac qualities. However, it is well known that chronic use of stimu-
lants will result in severe sexual dysfunction, including anorgasmia and lack
of sexual desire.
Opioids
Still very little is known about the morphinelike neurotransmitters,

the endorphins and enkephalines, and the beta-lipotropin in the pituitary
gland (Money, 1980). Endogenous opiates are involved centrally and periph-
erally. Endorphin activity has been found in many areas of the brain. The
enkephalins have been found in exceptionally high proportions in limbic
structures and in the hypothalamus, areas involved with emotionality, drive,
and stress responses. Endorphins have also been found peripherally in human
semen, in the prostate, and in the seminal vesicles. Opiates depress sexual
response and delay ejaculation in rats by inhibiting the contractions of the
vas deferens and seminal vesicles. Their central action is assumed to occur
through the hypothalamic-pituitary-testicular axis by inhibiting luteinizing
hormone-releasing factor. However, it has been suggested that they may
also act through the dopamine-serotonin pathways. The endogenous opiates
are released during sexual arousal and are, at least, partially responsible for
the sexual anesthesia and fuguelike state during sexual excitement. It has
long been known that opiates will enhance sexual arousal. It has also been
known that opium antagonists block many of these actions (Mclntosh,
Vallano, & Barfield, 1980; Murphy, 1981)
Many drug addicts have used opiates as a form of self-medication for
mental disorders (Verebey, Volavka, & Clouet, 1978). Opiates have been
reported to act in a way that reduces anxiety, rage, aggression, paranoia,
feelings of inadequacy, depression, and suicidal ideation (Khantzian, Mack,
& Schatzberg, 1974). When patients have been withdrawn from opiates,
many of these symptoms are manifested and then, again, controlled by
treating them with methadone. Opiates probably do not have direct control

over these symptoms but may reduce stress, which then alters many of the
other neurotransmitters involved in these emotional disorders. Chronic use
of opiates is associated with severe sexual dysfunction. This suggests that
opiates play a central role in regulation of sexual function (Crowley &
Simpson, 1978; Cushman, 1972).
When people are in danger, they produce high levels of natural opiates,
which can temporarily mask pain. It was found that people with PTSD
continue to produce those higher levels even after the danger has passed.
It has been suggested this may lead to the blunted emotions associated with
the condition (Yehuda, 1998).
It is theorized that a certain level of endorphin activity is needed
for normal psychological homeostasis. Altering endorphin levels through
exogenous opiates or through other medications, which indirectly affect
endorphin activity, may have therapeutic effects in some mental disorders.
It must be remembered that the inadequate level of endorphin activity in
some individuals may be due to the lack of endorphins that are released or
through problems with the receptors. It must also be remembered that the
endorphin system is only one of the active peptide systems in the central
nervous system. Behavior results from a complex interaction of the endorphin
system and all of the other peptide systems, including the well-known
neurotransmitter system. An imbalance in one of these systems or an alter-
ation through exogenous means may have a cascading effect on all the
systems that regulate mechanisms of the brain and, in turn, affect behavior.
As a result, attributing an effect in behavior to a deficiency or alteration
of one peptide mechanism is a gross oversimplification.
As illustrated in Figure 6.2, van der Kolk (1984) speculated that
neurotransmitter dysregulation explains repetition of traumaticlike experi-
ences. Reexposure to traumatic situations in humans evokes a central nervous
system opioid response. This response is analogous to that which is seen in
animals exposed to low-level shock after having been exposed to inescapable
shock. As a result of the endogenous release of opioid peptides, individuals
experience a sense of calm. As indicated earlier, opioid users describe psycho-
active effects such as reduction in anxiety, rage, aggression, paranoia, feelings
of anxiety, and depression. However, following release of opiate peptides,
withdrawal symptoms ensue. It is interesting to note that the symptoms of
PTSD parallel symptoms of opiate withdrawal. These common symptoms
include anxiety, outbursts of anger or aggressive behavior, sleep disturbances,
and hyperalertness. van der Kolk (1983) suggested that these seemingly
unrelated syndromes of opiate withdrawal and PTSD may involve common
neurological mechanisms that would include a decrease in brain opioid
receptor binding associated with central noradrenergic hyperactivity. So, in
the case of PTSD, reexposure to a traumatic situation would cause an
158 ELJCOLEMAN
Figure 6.2. Stress and its relationship to opioid activity.
endorphin response, which would give a paradoxical sense of calm and

reduction in anxiety, followed by physiological symptoms of opiate with-
drawal (increased anxiety, hyperreactivity, and outbursts of aggression).
Again, reexposure to a traumatic situation would relieve these
symptoms through release of opiate peptides. This cycle might explain
the biological drive to reexperience traumatic events. Or, in the case of
obsessive-compulsive disorder, this process may explain the senseless return
to behaviors that are often perceived to be unpleasant but create momentary
calm when one is engaging in these repetitive behaviors. So, this may be
part of the neurophysiochemical explanation of the perpetuating vicious
cycle of CSB.
Interrupting this vicious cycle is extremely difficult. This biological
process may explain why some of the abreaction techniques of psychotherapy
may not be helpful in treating trauma victims. As van der Kolk and col-
leagues stated:
If reliving the trauma is followed by a conditioned endorphin release
and subsequent withdrawal hyperreactivity, bringing back memories of
the trauma in a psychotherapeutic setting might actually increase
trauma-seeking behavior, as well as precipitate anxiety and explosive
outbursts of anger. Uncovering psychotherapy would thus lead to clinical
deterioration, (van der Kolk et al., 1985, p. 321)
NELJROANATOMICAL AND NEUROTRANSMITTER DYSFUNCTION 159

Methods to reduce autonomic hyperreactivity may be an important
bridge to recalling trauma and resolving the conflict without the individual
reexperiencing the trauma and evoking the vicious cycle of the stress re-
sponse (van der Kolk, McFarlane, & Weisaeth, 1996). Various pharmaco-
therapies can be powerful tools in reducing autonomic hyperreactivity
(J. R. T. Davidson & van der Kolk, 1996). Although cognitive and behavioral
psychotherapies and relaxation training designed to modify the conditioned
response could be effective (Rothbaum & Foa, 1996), one should recognize
the powerful and, oftentimes, resistant'to-change conditioned physiologi-
cal response.
PHARMACOLOGICAL TREATMENT
There are a number of pharmacologic treatments of CSB that have

proved effective in clinical case studies (Coleman et al., 2003; Raymond
et al., 2003).
Selective Serotonin Reuptake Inhibitors
Most of the recent attention to the treatment of CSB has been on

the effectiveness of the SSRIs. Given the efficacy of SSRIs in the treatment
of depression, anxiety, obsessive-compulsive disorder, and impulse-control
disorders, when the SSRIs came on the market in the late 1980s, a number
of open-label studies have indicated that the SSRIs may be efficacious in
the treatment of CSB (Bradford & Gratzer, 1995; Coleman et al., 1992;
Federoff, 1993;Kafka, 1991,1994; Kafka &Prentky, 1992; Stein etal., 1992).
These antidepressants that selectively act on serotonin levels in the
brain are effective in reducing sexual obsession and compulsions and their
associated levels of anxiety and depression. These medications appear to
interrupt the obsessive thinking and help patients control urges to engage
in CSB. They also help patients use therapy more effectively (Coleman
et al., 1992).
Because of the extensive case reports in the literature, clinicians often
choose these medications because of their wide efficacy in treating CSB but
also the very common psychiatric comorbidity (Black, Kehrberg, Flumerfelt,
& Schlosser, 1997; Raymond, Coleman, Ohlerking, Christenson, & Miner,
1999). The SSRIs have become the frontline medications for treating CSB
(Bradford, 2000).
Atypical Antidepresants
In my clinical experience, many patients with nonparaphilic CSB find

SSRIs helpful in controlling their sexual obsessions and compulsions but
160 ELI COLEMAN

have complained about the sexual side effects. These side effects are particu-
larly troublesome when the patients are trying to reestablish healthy sexual
and intimate functioning. Sexual side effects have often been cited as a
reason for patients discontinuing their SSRI medications, leading to a return
of sexual obsessions and compulsions.
Therefore, researchers began to shift a number of patients to nefaza-
done. Nefazadone has phenylpiperazine reuptake inhibitor effects and is a
competitive antagonist at the serotonin 5 HT2 receptor subtype. Antagonism
of 5 HT2 receptors has been associated with a lower incidence of sexual
side effects in comparison with standard SSRIs (Feiger, Kiev, Shrivastava,
Wisselink, & Wilcox, 1996). In a small retrospective study, it was found
that most of the patients (11 out of 14) who were switched from an SSRI
to long-term nefazodone therapy remained in reported good control or in
remission of their sexual obsessions and compulsions (Coleman, Gratzer,
Nescvacil, & Raymond, 2000).
Mood Stabilizers
Mood stabilizers can be used when appropriate. In fact, before the

advent of the SSRIs, my colleagues and I often used low doses of lithium
carbonate to treat cases of CSB. In one of our first published studies, we
successfully treated an individual with autoerotic asphyxia (Cesnik & Cole-
man, 1989). Although there was no evidence of cyclical mood disturbances,
this patient had dysthymia along with his self-destructive sexual behavior.
We did not consider antiandrogens because we felt that the underlying
depressive disorder was a key part of his ritualized behavior. Because most
of the older tricyclic antidepressants had been ineffective for treating this
type of problem in the past, my colleague had some clinical experience of
effectively using lithium carbonate with paraphilic behavior. Thus, we de-
cided on a trial of lithium carbonate. Although we did not completely
understand why the lithium carbonate was working, we began to speculate
that the serotonergic effects of this medication might be pharmacologic
action as well as lithium carbonate's known effectiveness in stabilizing cyclic
mood changes and decreasing aggressive and impulsive actions. This was a
significant case, as it opened the door to recognizing the importance of
using pharmacological treatment along with psychotherapy for a number of
cases of CSB. After the success of this case, we began to use this more
frequently until the advent of the SSRIs. Upon their arrival, we found the
SSRIs to be as effective and easier to administer. We began switching
patients to SSRIs with effective results (Coleman et al, 1992). However,
for some, the SSRIs were not sufficient in controlling their CSB, and we
began to use combinations of SSRIs and lithium carbonate and then other
mood stabilizers such as carbamazapine and valproic acid.

Antiandrogens
Medications that suppress the production of testosterone (antiandro-

gens) have also been used to treat a variety of paraphilic CSBs. Before the
advent of the SSRIs, these medications were the most common medications
used for treating CSB. The use of antiandrogens, such as cyproterone acetate
and medroxyprogesterone acetate, in the treatment of sex offenders was first
reported in 1968 (Money, 1968, 1970). Antiandrogen therapy essentially
replaced castration as a method of reducing testosterone because of its
relative reversibility and the ethical concerns involved. The antiandrogens
were problematic because of a variety of potential side effects, such as liver
disease, gynecomastia, thrombophlebitis, hyperglycemia, and gall bladder
disease. However, with the advent of the SSRIs, the use of antiandrogens
waned. SSRIs held an advantage over antiandrogens not only because of
their lower side-effect profile but because of their effectiveness in controlling
sexual obsessions and compulsions, their ease of administration, and their
ability to effectively treat many of the common comorbid psychiatric disor-
ders, especially anxiety and depressive disorders (Raymond et al., 1999).
There has been, however, a resurgence in the interest of antiandrogens
with the use of luprolide acetate. Leuprolide acetate is a synthetic analog
of leutinizing hormone-releasing hormone (LHRH), which is one of the
gonadotropin-releasing hormones. Therefore leuprolide acetate is a potent
LHRH agonist. Initially leuprolide acetate stimulates the release of produc-
tion of testosterone and other testicular steroids, but with chronic adminis-
tration testicular steroidogenesis is suppressed. Luprolide acetate has been
reported to cause fewer side effects, although there still is a concern about
osteopenia (Thibaut, Cordier, & Kuhn, 1993, 1996). Apart from the afore-
mentioned studies, there have been a number of other reports, including
in our own clinic, which have had successful outcomes (Dickey, 1992;
Raymond, Robinson, Kraft, Rittberg, & Coleman, 2002).
Naltrexone
There has been a recent interest in the use of naltrexone in the

treatment of CSB. This stems from the discovery of its effectiveness in
treating a variety of urge-driven disorders, such as pathological gambling
disorder (Kim & Grant, 2001; Kim, Grant, Adson, & Shin, 2001), kleptoma-
nia (Grant & Kim, 2002), alcoholism (Volpicelli, Alterman, Hayashida, &.
O'Brien, 1992), borderline personality disorder with self-injurious behavior
(Sonne, Rubey, &. Brady, 1996), and eating disorders (e.g., Marrazzi, Bacon,
Kinzie, & Luby, 1995). My colleagues and I reported on the first successful
treatment of two individuals with CSB with naltrexone (Raymond, Grant,
Kim, & Coleman, 2002). Both individuals had severe CSB symptoms and
162 ELI COLEMAN

had only shown mild improvements with SSRIs and other antidepressants.
When naltrexone was added to the SSRI treatment, the patients lost urges
to engage in their prior problematic behavior and were able to stop their CSB.
One can only speculate in these cases on the pharmacologic action.
However, if the patients had a dysregulation of the opioid system, the use
of naltrexone, an opioid antagonist, would make sense. However, these
results are obviously preliminary, and there have not been many other
patients who have responded positively in this fashion.
There is an obvious need for controlled clinical trials to develop a
more evidenced-based clinical approach to pharmacologic treatment. How-
ever, these case studies illustrate the need for careful consideration of the
array of treatment options, careful monitoring of CSB symptoms, and the
willingness of the physician and patient to try different options when a
certain medication is failing. This is not to say that there is a pharmacologic
panacea out there for every case of CSB; however, it does illustrate that
sometimes the right medication or combination of medications will help
resolve the symptoms.
Pharmacological Therapy as an Adjunct to Psychotherapy
As a consequence, pharmacological agents can be extremely helpful

in interrupting the vicious cycle of CSB. The psychotherapist may need an
important ally in these agents as he or she helps the individual to engage
in the stressful experience of psychotherapy, as well as to gain more rapid
control of CSB. In psychotherapy, individuals with CSB are often asked to
recall their childhood abusive experiences. This reexperiencing of the trauma
initially evokes a surprisingly calm or detached response. This is often
followed by increased anxiety, which does not seem to be necessarily triggered
by any particular event. Or, an emotional response to a particular event
(e.g., rejection) is felt far more acutely than the situation would warrant.
As clinicians, we are often puzzled by the repeated or compulsive
behaviors that ultimately produce far more negative feelings than the brief
temporary relief that a CSB can produce. These neurophysiological mecha-
nisms might help explain how the psychodynamic drives are also regulated
by neurochemical changes that occur in the brain (increase in synthesis
providing psychic relief followed by increased emotional distress).
CONCLUSION
Pharmacological treatments that address neuroanatomical abnormali-

ties, disturbances, or neurotransmitter dysregulation can be very helpful in
assisting individuals with CSB. These disturbances may have been a result

of congenital abnormalities, inherited predispositions, or trauma. Physical
or psychic trauma can lead to a variety of neuroanatomical or neurophysio-
logical disturbances. No simple brain mechanism or neurotransmitter
dysfunction or dysregulation will explain the complexity of human sexual
expression or disorders. However, there should be great optimism for further
understanding the neurophysiological abnormalities and their relationship
to sexual behavior.
There is now an array of pharmacotherapies that can address a variety
of possible dysfunctions. Individual differences in neurotransmitter activity
because of congenital or environmental influences may explain an individu-
al's neurotransmitter dysregulation and why some medications are more
helpful to some than to others. However, pinpointing the cause or the cure
is further complicated by the fact that there are complex interactions of
stress, individual responsivity, environmental factors, neurotransmitters, and
receptors that account for a person's behavior.
Physiological explanations of the CSB are inadequate to fully under-
stand the etiology. However, these physiological explanations may help
explain the biological underpinnings of the psychological theories of CSB.
In addition, these physiological processes also have important implications
for psychotherapy. As a result, the clinician might find pharmacotherapy
extremely helpful in treating individuals with CSB, not only in gaining
rapid control of CSB but also in helping the patient be more responsive to
the rigors and stressors of psychotherapy.
REFERENCES
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental

disorders (4th ed., text revision). Washington, DC: Author.
Bancila, M., Verge, D., Rampin, O., Backstrom, J. R., Sanders-Bush, E., McKenna,
K. E., et al. (1999). 5-Hydroxytryptamine 2C receptors on spinal neurons
Bancroft, J. (1977). Hormones and sexual behaviour. Psychological Medicine, 7, 553-
556.
Berlin, F. (1988). Issues in the exploration of biological factors contributing to the
etiology of the "sex offender," plus some ethical considerations. Annals of the
New York Academy of Sciences, 528, 183-192.
Bitran, D., & Hull, E. M. (1987). Pharmacological analysis of male rat sexual
behavior. Neuroscience and Biobehavioral Review, 11, 365-389.
Black, D. W., Kehrberg, L. L, Flumerfelt, D. L, & Schlosser, S. S. (1997). Charac-
teristics of 36 subjects reporting compulsive sexual behavior. American Journal
164 ELICOLEMAN
Blumer, D. (1970). Hypersexual episodes in temporal lobe epilepsy. American Journal
Blumer, D., & Walker, A. E. (1967). Sexual behavior in temporal lobe epilepsy.
Archives of Neurology, 16(1), 37-43.
Bradford, J. (2000). Treatment of sexual deviation using a pharmacologic approach.
journal of Sex Research, 37, 248-257.
Bradford, J. M. W., &. Gratzer, T. G. (1995). A treatment for impulse control
disorders and paraphilia: A case report. Canadian Journal of Psychiatry, 40, 4-5.
Cesnik, J. A., & Coleman, E. (1989). Use of lithium carbonate in the treatment
of autoerotic asphyxia. American Journal of Psychotherapy, 43, 277-286.
Coleman, E. (1990). The obsessive-compulsive model for describing compulsive
sexual behavior. American Journal of Preventative Psychiatry and Neurology,
2(3), 9-14.
Coleman, E. (1991). Compulsive sexual behavior: New concepts and treatments.
Journal of Psychology and Human Sexuality, 4, 37-52.
Coleman, E. (1992). Is your patient suffering from compulsive sexual behavior?
Psychiatric Annals, 22, 320-325.
Coleman, E. (1995). Treatment of compulsive sexual behavior. In R. C. Rosen &
S. R. Leiblum (Eds.), Case studies in sex therapy (pp. 333-349). New York:
Guilford Press.
Coleman, E. (2003). Compulsive sexual behavior: What to call it, how to treat it?
SIECUS Report, 3 1 ( 5 ) , 12-16.
Coleman, E., Cesnik, J., Moore, A., & Dwyer, S. M. (1992). An exploratory study
of the role of psychotropic medications in the treatment of sex offenders.
Journal of Offender Rehabilitation, 18(3/4), 75-88.
Coleman, E., Gratzer, T., Nescvacil, L., & Raymond, N. (2000). Nefazodone and
the treatment of nonparaphilic compulsive sexual behavior: A retrospective
study. Journal of Clinical Psychiatry, 61, 282-284.
Coleman, E., Raymond, N., &. McBean, A. (2003). Assessment and treatment of
compulsive sexual behavior. Minnesota Medicine, 86(7), 42-47.
Crowley, T. J., & Simpson, A. (1978) Methadone dose and human sexual behavior.
International Journal of Addiction, 31, 285-295.
Cushman, P. (1972). Sexual behavior in heroin addiction and methadone mainte-
nance: Correlation with plasma luteinizing hormone. New York State Journal
of Medicine, 72, 1261-1265.
Damasio, A. R., Tranel, D., & Damasio, H. (1990). Individuals with sociopathic
behavior caused by frontal damage fail to respond autonomically to social
stimuli. Behavioural Brain Research, 41, 81-94-
Davidson, J. R. T., & van der Kolk, B. A. (1996). The psychopharmacological
treatment of posttraumatic stress disorder. In B. A. van der Kolk, A. C.
McFarlane, &. L. Weisaeth (Eds.), Traumatic stress: The effects of overwhelming
experience on mind, body and society (pp. 510-524). New York: Guilford Press.
NEUROANATOMICAL AND NEUROTRANSM1TTER DYSFUNCTION 165

Davidson, R. J., Jackson, D. C., & Kalin, N. H. (2000). Emotion, plasticity, context,
and regulation: Perspectives from affective neuroscience. Psychological Bulletin,
126, 890-909.
Dickey, R. (1992). The management of a case of treatment-resistant paraphilia
with a long-acting LHRH agonist. Canadian Journal of Psychiatry, 37, 567-569.
Elliot, M. L., & Biever, L. S. (1996). Head injury and sexual dysfunction. Brain
Injury, 10, 703-717.
Federoff, J. P. (1993). Serotonergic drug treatment of deviant sexual interests. Annals
of Sex Research, 6, 105-121.
Feiger, A., Kiev, A. Shrivastava, R. K., Wisselink, P. G., & Wilcox, C. S. (1996).
Nefazodone versus sertraline in outpatients with major depression: Focus on
efficacy, tolerability, and effects on sexual function and satisfaction. Journal of
Clinical Psychiatry, 57(Suppl. 2), 53-62.
Frohman, E. M., Frohman, T., & Moreault, A. M. (2002). Acquired sexual para-
philia in patients with multiple sclerosis. Archives of Neurology, 59, 1006-1010.
Gessa, G. L., & Tagliamonte, A. (1974). Possible role of brain serotonin and
dopamine in controlling male sexual behavior. Advances in Biochemical Psycho*
pharmacology, 11(0), 217-228.
Goscinski, I., Kwiatkowski, S., Polak, J., Orlowiejska, M., & Partyk, A. (1997).
The Kluver-Bucy syndrome. Journal of Neurological Sciences, 41, 269-272.
Grant, J. E., & Kim, S. W. (2002). An open label study of naltrexone in the
treatment of kleptomania. Journal of Clinical Psychiatry, 63, 349-56.
Huws, R., Shubsachs, A. P., & Taylor, P. J. (1991). Hypersexuality, fetishism and
multiple sclerosis. British Journal of Psychiatry, 158, 280-281.
Kafka, M. P. (1991). Successful antidepressant treatment of nonparaphilic sexual
addictions and paraphilias in men. Journal of Clinical Psychiatry, 52(2), 60-65.
Kafka, M. P. (1994). Sertraline pharmacotherapy for paraphilias and paraphilia-
related disorders: An open trial. Annals of Clinical Psychiatry, 6, 189-195.
Kafka, M. P., & Coleman, E. (1991). Serotonin and paraphilias: The convergence
of mood, impulse and compulsive disorders [Letter]. Journal of Clinical Psycho-
pharmacology, I I , 223-224.
Kafka, M. P., & Prentky, R. (1992). Fluoxetine treatment of nonparaphilic sexual
addictions and paraphilias in men. Journal of Clinical Psychiatry, 53(10), 351-
358.
Khantzian, E. J., Mack, J. E., & Schatzberg, A. F. (1974). Heroin use as an attempt
to cope: Clinical observations. American Journal of Psychiatry, 131, 160-164.
Kim, S. W., &. Grant, J. E. (2001). An open naltrexone treatment study in pathologi-
cal gambling disorder. International Journal of Clinical Psychopharmacology,
16, 285-289.
Kim, S. W., Grant, J. E., Adson, D., & Shin, Y. C. (2001). Double-blind naltrexone
and placebo comparison study in the treatment of pathological gambling.
Biological Psychiatry, 49, 914-921.
166 ELI COLEMAN

Kluver, H., &. Bucy, P. C. (1939). Preliminary analysis of functions of the temporal
lobes in monkeys. Archives of Neurological Psychiatry, 42, 979-1000.
Kolarsky, A., Madlafousek, J., & Novotna, V. (1978). Stimuli eliciting sexual
arousal in males who offend adult women: An experimental study. Archives of
Sexual Behavior, 7(2), 79-87.
Kolb, L. C., Burris, B. C., & Griffiths, S. (1984). Propanolol and clonidine in the
treatment of the chronic post traumatic stress disorders of war. In B. A. van
der Kolk (Ed.), Post traumatic stress disorder: Psychological and biological sequelae
(pp. 97-107). Washington, DC: American Psychiatric Press.
Kolb, L. C., & Mutalipassi, L. R. (1982). The conditioned emotional response: A
subclass of the chronic and delayed post-traumatic stress disorders. Psychiatric
Annals, 12, 979-987.
Lane, R. M. (1997). A critical review of selective serotonin reuptake inhibitor-
related sexual dysfunction: Incidence, possible aetiology and implications for
management. Journal of Psychopharmacology, 11, 72-82.
Langevin, R. (1990). Sexual anomalies and the brain. In W. L. Marshall, D. R.
Laws, & H. E. Barbaree (Eds.), Handbook of sexual assault (pp. 103-113). New
York: Plenum.
LeDoux, J. (1998). Fear and the brain: Where have we been, and where are we
going? Biological Psychiatry, 44, 1229-1238.
Marrazzi, M. A., Bacon, J. P., Kinzie, J., & Luby, E. D. (1995). Naltrexone use in
the treatment of anorexia nervosa and bulimia nervosa. International Clinical
Psychopharmacology, 10, 163-172.
Marson, L., & McKenna, K. E. (1992). A role for 5-hydroxytryptamine in descend-
ing inhibition of spinal sexual reflexes. Experimental Brain Research, 88, 313-
320.
Mclntosh, T.K., Vallano, M. L., & Barfteld, R.J. (1980). Effects of morphine,
B-endorphin and naloxone on catecholamine levels and sexual behavior in
the male rat. Pharmacology, Biochemistry and Behavior, 13, 435-441.
Mendelson, J. H., & Mello, N. K. (1974). Alcohol, aggression and androgens. In
S. H. Frazier (Ed.), Aggression (Vol. 52, pp. 225-247). Baltimore: Williams
& Wilkins.
Mendez, M. F., Chow, T., Ringman, J., Twitchell, G., & Hinkin, C. H. (2000).
Pedophilia and temporal lobe disturbances. Journal ofNeuropsychiatry and Clini-
cal Neurosciences, 12(1), 71-76.
Mesulam, M. M. (1981). Dissociative states with abnormal temporal lobe EEG:
Multiple personality and the illusion of possession. Archives of Neurology,
38, 176-181.
Miller, B., Cummings, J. L., Mclntyre, H., Ebers, G., &Grode, M. (1986). Hypersex-
uality or altered sexual preference following brain injury. Journal of Neurology,
Neurosurgery, and Psychiatry, 49, 867-873.
Modell, J. G., Katholi, C. R., Modell, J. D., & DePalma, R. L. (1997) Comparative
sexual side effects of bupropion, fluoxetine, paroxetine, and sertraline. Clinical
Pharmacolog)! and Therapeutics, 61, 476-487.
NEUROANATOMICAL AND NEVROTRANSMITTER DYSFUNCTION 167

Money, J. (1968). Discussion on hormonal inhibition of libido in male sex offenders.
In R. P. Michael (Ed.), Endocrinology and human behaviour (p. 169). London:
Oxford University Press.
Money, J. (1970). Use of androgen-depleting hormone in the treatment of male
sex offenders. Journal of Sex Research, 6, 165-172.
Money, J. (1980) Love and love sickness: The science of sex., gender differences, and
pair bonding. Baltimore: Johns Hopkins University Press.
Money, J. (1990). Forensic sexology: Paraphilic serial rape (biastophilia) and lust
murder (erotophonophilia) American Journal of Psychotherapy, 44(1), 26-36.
Money, J., & Lamarz, M. (1990). Vandalized lovemaps. Buffalo, NY: Prometheus
Press.
Monga, T. N., Monga, M., Raina, M. S., &.Hardjasudarma, M. (1986). Hypersexual-
ity in stroke. Archives of Physical Medicine and Rehabilitation, 67, 415-417.
Murphy, M. R. (1981). Methadone reduces sexual performance and sexual motiva-
tion in male Syrian golden hamster. Pharmacology, Biochemistry and Behavior,
14, 561-567.
Nakada, T., Lee, H., Kwee, I. L., & Lerner, A. M. (1984). Epileptic Kluver-Bucy
syndrome: Case report. Journal of Clinical Psychiatry, 45(2), 87-88.
Ortego N., Miller, B. L., Itabashi, H., & Cummings, J. L. (1993). Altered sexual
behavior with multiple sclerosis: A case report. Neuropsychiatry, Neuropsychol-
ogy, & Behavioral Neurology, 6, 260-264.
Pearce, J., & Miller, E. (1973). Clinical aspects of dementia. London: Ballilliere,
Tyndall.
Rada, R., Kellner, R., & Winslow, W. (1976). Plasma testosterone and aggressive
behavior. Psychosomatics, 17, 138-142.
Rada, R. T., Laws, D. R., & Kellner, R. (1976). Plasma testosterone levels in the
rapist. Psychosomatic Medicine, 38, 257-268.
Raymond, N. C., Coleman, E., Benefield, C., & Miner, M. (2003). Psychiatric
comorbidity and compulsive/impulsive traits in compulsive sexual behavior.
Comprehensive Psychiatry, 44(5), 370-380.
Raymond, N. C., Coleman, E., Ohlerking, F., Christenson, G. A., & Miner, M.
(1999). Psychiatric comorbidity in pedophilic sex offenders. American Journal
Raymond, N. C., Grant, J. E., Kim, S. M., & Coleman E. (2002). Treatment of
compulsive sexual behavior with naltrexone and serotonin reuptake inhibitors:
Two case studies. International Clinical Psychopharmacology, 17, 201-205.
Raymond, N. C., Robinson, B. E., Kraft, C., Rtttberg, B., & Coleman, E. (2002).
Treatment of pedophilia with leuprolide acetate: A case study. Journal of
Psychology and Human Sexuality, 13(3/4), 79-88.
Rothbaum, B. O., & Foa, E. B. (1996). Cognitive-behavioral therapy for posttrau-
matic stress disorder. In B. A. van der Kolk, A. C. McFarlane, &. L. Weisaeth
(Eds.), Traumatic stress: The effects of overwhelming experience on mind, body
and society (pp. 491-509). New York: Guilford Press.
168 ELI COLEMAN

Sonne, S., Rubey, R., & Brady, K. (1996). Naltrexone treatment of self-injurious
thoughts and behaviors. Journal of Nervous and Mental Disorders, 184, 192-195.
Stein, D. J., Hollander, E., Anthony, D. T., Schneier, F. R., Fallen, B. A., Liebowitz,
M. R., & Klein, D. F. (1992). Serotonergic medications for sexual obsessions,
sexual addictions and paraphilias. Journal of Clinical Psychiatry, 53, 267-271.
Steinbusch, H. (1981) Distribution of serotonin-immunoreactivity in the central
nervous system of the rat-cell bodies and terminals. Neuroscience, 6, 557-618.
Stoller, R. J. (1975). Perversion: The erotic form of hatred. New York: Pantheon.
Thibaut, F., Cordier, B., & Kuhn, J. M. (1993). Effect of a long-lasting gonadotro-
phin hormone-releasing hormone agonist in six cases of severe male paraphilia.
Acta Psychiatria Scandanavia, 87, 445-450.
Thibaut, F., Cordier, B., & Kuhn, J. M. (1996). Gonadotrophin hormone releasing
hormone agonist in cases of severe paraphilia: A lifetime treatment? Psychoneu-
roendocrinology, 21, 411-419.
van der Kolk, B. A. (1983). Psychopharmacological issues in posttraumatic stress
disorder. Hospital and Community Psychiatry, 34, 683-691.
van der Kolk, B. A. (Ed.). (1984). Post traumatic stress disorder: Psychological and
biological sequelae. Washington, DC: American Psychiatric Press.
van der Kolk, B. A. (1988). The trauma spectrum: The interaction of biological
and social events in the genesis of the trauma response, journal of Traumatic
Stress, I, 273-290.
van der Kolk, B. A., Greenberg, M., Boyd, H., & Krystal, J. (1985). Inescapable
shock, neurotransmitters, and addiction to trauma: Toward a psychobiology
of post traumatic stress. Biological Psychiatry, 20, 314-325.
van der Kolk, B. A., McFarlane, A. C, & Weisaeth, L. (Eds.). (1996). Traumatic
stress: The effects of overwhelming experience on mind, body and society. New
York: Guilford Press.
Verebey, K., Volavka, J., & Clouet, D. (1978). Endorphins in psychiatry. Archives
of General Psychiatry, 35, 877-888.
Volpicelli, J. R., Alterman, A. I., Hayashida, M., & O'Brien, C. P. (1992). Naltrex-
one in the treatment of alcohol dependence. Archives of General Psychiatry,
49, 876-880.
Yehuda, R. (1998). Psychoneuroendocrinology of post-traumatic stress disorder.
Psychiatric Clinics of North America, 21, 359-379.

SYNTHESIS: OVERARCHING
THEMES AND FUTURE DIRECTIONS
FOR RESEARCH
JANET SHIBLEY HYDE AND BEVERLY WHIPPLE
In this volume, readers have found a dazzling array of results from the
very cutting edge of research on the biological substrates of human sexuality.
A wide range of behaviors and identities have been considered, including
erection, orgasm, compulsive sexual behavior, homosexuality, transsexu-
alism, and orgasm in women with spinal cord injury. The array of biological
substrates is equally broad and includes genes, neurotransmitters, hormones,
brain regions, the spinal cord, and peripheral nerves. In this final chapter,
we synthesize this material, first considering overarching themes across the
chapters, and then considering future directions for research.
OVERARCHING THEMES
Several overarching themes emerged across the chapters of this volume:

Biological substrates are developmental; sexuality is complex and multifaC'
eted; certain regions of the brain have been identified as key for sexuality,
171
and the spinal cord is crucial as well; and the biological substrates of human
sexuality involve multiple interlocking systems.
Biological Substrates Are Developmental
Traditional models regard biological influences as fixed and what people

are born with. Modern neuroscience research tells a very different tale. For
example, in both rats and humans there are differences between males and
females in the sexually dimorphic nucleus of the preoptic area (SDN-POA)
in the hypothalamus. However, in humans this difference appears only after
the 4th year of age (Swaab & Hofman, 1988)—that is, it is not present
from birth! As a second and more well-known example, sex hormone levels
rise dramatically at puberty. Biological phenomena may emerge or disappear
at various times across the life span.
Sexuality Is Complex and Multifaceted
Behavioral research on human sexuality provides abundant evidence of

its complexity. In humans, for example, there can be marked inconsistencies
between the individual's sexual identity (heterosexual, homosexual, or bi-
sexual) and the person's sexual orientation defined behaviorally (Lever,
Kanouse, Rogers, Carson, & Hertz, 1992). Some women, for example, think
of themselves as lesbians but occasionally sleep with men. Other women
think of themselves as bisexual yet have had sex only with men. Some men
think of themselves as heterosexual yet occasionally have sex with men.
As another example, if we consider male-to-female transsexuals, they
fall into two subcategories: androphilic and gynephilic (Blanchard, Dickey,
& Jones, 1995). This refers to their sexual orientation following sex change.
That is, some male-to-female transsexuals are attracted to men (androphilic),
and others are attracted to women (gynephilic). As one can see from ques-
tions of sexual orientation and transsexualism, then, sexuality is complex,
and the complexity only expands when we consider other aspects of sexuality.
Because human sexuality is so complex, the biological substrates are
complex, and simple models will be inadequate. As described in chapter 2,
even in the lowly fruitfly Drosophila, sexual behavior involves multiple
components, including discriminating conspecifics from members of other
species, discriminating male from female conspecifics, searching for a mate,
courtship (which includes specific behaviors such as tapping, singing, and
licking), and copulation. Geneticists have identified at least 14 specific
genes that form the substrates for each of these components (Emmons &
Lipton, 2003). Human sexuality is vastly more complex, and the biological
mechanisms underlying it must be comparably complex.
172 HYDE AND WH1PPLE

Key Regions of the Brain
Certain regions of the brain have been implicated repeatedly in research

on sexual behavior: the hypothalamus, the bed nucleus of the stria terminalis
(BST), the brainstem, and the frontal and temporal lobes.
In the hypothalamus, one crucial region is the SDN-POA, also known
as the interstitial nucleus of the anterior hypothalamus (INAH-1). It is
termed the sexually dimorphic nucleus because it is approximately twice as
large in young adult men compared with women (Swaab, chap. 3, this
volume). In animal models, lesions to this region eliminate mounting, intro-
mission, and ejaculation, although erection still occurs (McKenna, 1998).
The evidence indicates that there are more androgen receptors in men
compared with women in several hypothalamic regions (Swaab, chap. 3,
this volume). The para ventricular nucleus (PVN) of the hypothalamus has
been implicated in erection in males. Moreover, Komisaruk and Whipple's
research (chap. 5, this volume) using functional magnetic resonance imaging
(fMRI) indicates activation of the PVN during orgasm in women. Several
regions of the limbic system (including amygdala and hippocampus) are
activated as well.
The BST is located adjacent to the hypothalamus, septum, and
amygdala. One region shows a marked sexual dimorphism. In male-to-female
transsexuals, this region is female-sized, suggesting that it may play a role
in core gender identity (Swaab, chap. 3, this volume).
As McKenna (chap. 4, this volume) discusses, the brainstem (medulla
and pons) is involved in inhibition of spinal sexual reflexes, which are
discussed in the next section. Many of these brainstem neurons are serotoner-
gic and may be the mechanisms by which the selective serotonin reuptake
inhibitor (SSRI) antidepressants create sexual dysfunctions.
The frontal lobes of the brain are responsible for executive functioning;
applied to sexuality, this refers to appropriate inhibition of certain responses,
including sexual responses. As Coleman (chap. 6, this volume) notes, com-
pulsive sexual behavior may be linked to abnormalities of the frontal lobes
that reduce inhibitory control of behavior. The temporal lobe has been
implicated in numerous studies, such as those showing hypersexuality in
patients following a stroke that produced lesions to the temporal lobe (Cole-
man, chap. 6, this volume). Whether these effects are due to damage to the
temporal cortex or to the underlying hippocampus and amygdala is unclear.
The Spinal Cord
As McKenna (chap. 4, this volume) discusses, the spinal cord is also

crucial to sexual behavior. Both sympathetic and parasympathetic systems
are involved. Sensory nerves innervate the sexual organs. In spinal reflex
SYNTHESIS 173
mechanisms, these sensory nerves pass to interneurons at various levels of
the spinal cord, which in turn activate neurons involved in sexual functions
such as erection and orgasm. Individuals with spinal cord injury and associ-
ated difficulties with sexual functioning provide tangible evidence of the
role of the spinal cord in sexuality.
Despite this extensive evidence that all sexual pathways lead through
the spinal cord, Komisaruk and Whipple (chap. 5, this volume) have found
remarkable evidence of a second, alternative pathway in women with com-
plete spinal cord injury and in women without spinal cord injury as well.
Some women with diagnosed complete spinal cord injury report experiencing
orgasms during sexual activity. Komisaruk and Whipple's research indicates
a crucial role for the sensory Vagus nerves, compared with the hypogastric,
pudendal, and pelvic nerves that have traditionally been regarded as the
transmitters of sexual sensations and enter the spinal cord at T10 or below.
Komisaruk and Whipple's research participants, with complete spinal cord
injury at T10 or above, should not have been able to experience genital
sensations, much less orgasm. Anatomical research indicates that the Vagus
extends to the uterus and cervix, and its ascending pathway passes completely
outside the spinal cord, up through the neck to a region of the medulla
called the nucleus of the solitary tract (NTS). Their fMRI studies indicate
that cervical self-stimulation in women with complete spinal cord injury
above T10 results in activation of the NTS. Their research with noninjured
women indicates activation of t,he PVN of the hypothalamus during orgasm.
Multiple, Interlocking Systems
Modern neuroscience research pays tribute to the principle that genes,

the brain, and the endocrine system can no longer be considered separately.
Rather, they are interlocking systems that involve interactive processes.
Swaab provided an excellent example in chapter 3. The SRY gene on the Y
chromosome directs prenatal differentiation of the testes, which then begin
manufacturing testosterone abundantly during the prenatal period. This tes-
tosterone then acts on the developing hypothalamus, differentiating it in a
sexually dimorphic manner. One characteristic of the male-differentiated
hypothalamus is that it contains more androgen receptors than the female-
differentiated hypothalamus.
As another example, positron emission tomography (PET) and fMRI
studies in humans indicate that the PVN of the hypothalamus is activated
during orgasm in women (Komisaruk & Whipple, chap. 5, this volume).
The PVN secretes oxytocin, creating a surge of oxytocin in the bloodstream
following orgasm, which may account for feelings of a desire for bonding
following orgasm (Swaab, chap. 3, this volume). This illustrates how periph-
174 HYDE AND WHIPPLE

eral stimulation and sensations are linked to brain activity, hormone release,
and psychological responses.
FUTURE DIRECTIONS
The impressive new research reviewed in this volume encourages us

to ask where we will or should go in research in the next decade. Here we
suggest several of the strong possibilities.
Advances in Research Technology
The rapid advances in research on the biological substrates of sexuality

have been made possible because of enormous advances in research tech-
niques and technologies. Perhaps most important are the advances in scan-
ning technology represented by PET and fMRI. They allow monitoring of
specific brain regions in alive, awake, behaving humans and place us light
years ahead of traditional techniques such as dissection of cadavers. The
time and energy of many researchers will be needed over the next decade
to fully exploit the possibilities of these technologies for sex research.
Even these advanced technologies have certain limitations. Measure-
ments are not made in a person's or couple's natural setting. Participants'
movement is severely restricted. Moreover, only those persons who are
comfortable with sexual self-stimulation in a laboratory setting can provide
research data currently. This last limitation leads to a highly selective
research sample, which in turn leads to questions about the extent to which
the results can be generalized to the rest of the population. Technological
advances that overcome these limitations will surely help the field advance.
Advances in animal studies of sexual function are being made with
new neuroanatomical techniques. One such technique, the c-fos method,
takes advantage of the fact that some neurons express the early intermediate
gene c-fos following strong activation. The c-fos can be identified by staining
after the experiment. This allows experimenters to identify neurons that
were activated during the course of some stimulus, activity, or even complex
behavior. This method can be combined with traditional neuroanatomical
techniques, such as tract tracing and immunochemistry to identify the
connections and neurochemistry of the c-fos labeled neurons. Stimulation
and lesion studies can further verify the functional role of the labeled
neurons. A limitation of this technique is that not all neurons express
c-fos following activation. Thus, the method gives an incomplete picture.
Furthermore, great care must be taken in experimental design to ensure
that the differences between experimental and control animals are due only
SYNTHESIS 175
to a specific stimulus or behavior. Nonetheless, this technique has led to a
number of important advances.
Another novel method is the use of transneuronal labeling techniques.
This involves the use of viruses that infect neurons. The virus is injected
into a specific organ, where it is picked up by nerve terminals and retrogradely
transported back to the cell body. The virus replicates and is shed by the
neuron, where it is picked up by nerve terminals synapsing on the infected
cell. The process then continues to the next step. This allows identification
of neurons that contribute to the innervation of a given organ, even a
number of synapses removed. The functional role of neurons identified in
this way can be examined by lesion and stimulation experiments. This
technique has also provided valuable insights into the innervation of pelvic
organs and the central nervous system control of sexual function.
The Importance of Accurate Measurement and Diagnosis
Research on biological substrates has often been hampered by flaws

in the measurement or diagnosis of the behavioral phenotype. For example,
research on the genetics of sexual orientation has tended to treat all male
homosexuals as a single category, despite credible evidence of multiple
subcategories (Bell & Weinberg, 1978). Among lesbians, there is the distinc-
tion between lifetime lesbians (who have been lesbian ever since they
became sexual) and adult lesbians (who were heterosexual and became
lesbian in midlife; Valanis et al., 2000). It may be that there is strong genetic
influence on one type of homosexuality but not on others. Until we are
more proficient in measuring and identifying the behavioral phenotype,
genetic research will be hampered.
The Importance of Interdisciplinary Collaborations
Further advances in research on the biological substrates of human

sexuality will depend on interdisciplinary collaborations among researchers
from psychology and neuroscience and clinicians. Practicing clinicians often
have the best knowledge of particular patterns of disturbed sexual behavior
that are in need of explanation and treatment. In a sense, they are the
frontline observers. Their experience in treating sexual problems and para-
philias with drugs can provide valuable research leads, insofar as drug treat-
ment at the cutting edge is often more a matter of discovering "what works"
than of administering a well-validated protocol. Research psychologists have
important contributions to make in the measurement and diagnosis of behav-
ior, as well as from their own expertise in neuroscience. Neuroscientists
help by importing the latest developments in neuroanatomy, neurophysiol-
ogy, and endocrinology, for their potential applications in the study of

sexuality. These future collaborations should be extremely fruitful, and the
complexity of human sexuality provides ample demonstration of the need
for multidisciplinary approaches.
Addressing Relationship Issues
Understanding the sexual behavior of the individual, and its biological

substrates, is an enormous challenge, but one on which considerable progress
has been made in the last decade. Human sexual behavior, however, usually
occurs in the context of an interaction between two people. An important
next task is to understand better the relational aspects of sexuality, their
biological bases in the two individuals, and possible biological interactions
between individuals, such as pheromonal communication.
An illustrative example and cautionary tale come from the research
and hidden assumptions that led up to the release of Viagra. The research
focused on developing a drug that would enable men with erectile disorder
to have erections, certainly a worthy goal. In the process, the men's female
partners were ignored, or it was assumed that they would be delighted with
their men's newfound erections (Potts, Gavey, Grace, & Vares, 2003).
Almost as soon as Viagra was released, however, cases began to surface in
which partners were not delighted, for several reasons: Some had become
quite accustomed to the absence of erections and absence of sexual activity
and liked it that way; others felt that they were being coerced into sex by
overeager men and their overeager erections. In short, Viagra can create
relationship problems. Moreover, it cannot cure erectile disorders that are
a result of relationship problems.
Researchers are just beginning to study the effects of having the female
partner act as an equal partner in treatment decisions (Leiblum, 2002).
Data are beginning to suggest that if the female partner is involved in the
initial assessment of erectile disorder and if she is involved in the decision
process as to what treatment will be acceptable to both, there is better
compliance. Future research on the biological substrates of human sexuality
must take on the challenge of addressing the relational aspects of sexuality.
CONCLUSION
Research on the biological substrates of human sexuality has advanced

in spectacular ways in the past 15 years. At the same time, we have many miles
to go. We must find methods that enable us to study integrated models of
biological, psychological, relational, and sociocultural influences. And what-
ever the final outcomes are in research on neural pathways, neurotransmitters,
SYNTHESIS 177
and hormones, we must not lose sight of the plasticity of these biological
systems and the sexual behaviors associated with them.
REFERENCES
Bell, A. P., & Weinberg, M.S. (1978). Homosexualities, New York: Simon &
Schuster.
Blanchard, R., Dickey, R., & Jones, C. L. (1995). Comparison of height and weight
in homosexual versus nonhomosexual gender dysphorics. Archives of Sexual
Behavior, 24, 543-554.
Emmons, S. W., & Lipton, J. (2003). Genetic basis of male sexual behavior. Journal
ofNeurobiology, 54, 93-110.
Leiblum, S. R. (2002). After sildenafil: Bridging the gap between pharmacologic
treatment and satisfying sexual relationships. Journal of Clinical Psychiatry,
63(Suppl. 5), 17-22.
Lever, J., Kanouse, D. E., Rogers, W. H., Carson S., & Hertz, R. (1992). Behavior
patterns and sexual identity of bisexual males. Journal of Sex Research, 29, 141-
167.
McKenna, K. E. (1998). Central control of penile erection. International Journal of
Impotence Research, W, S25-S34.
Potts, A., Gavey, N., Grace, V., & Vares, T. (2003). The downside of Viagra:
Women's experiences and concerns. Sociology of Health & Illness, 25, 697-719.
Swaab, D. F., &. Hofman, M. A. (1998). Sexual differentiation of the human hypo-
thalamus: Ontogeny of the sexually dimorphic nucleus of the preoptic area.
Valanis, B. G., Bowen, D. J., Bassford, T., Whitlock, E., Charney, P., &. Carter,
R. A. (2000). Sexual orientation and health: Comparisons in the Women's
Health Initiative sample. Archives of Family Medicine, 9, 843-853.

AUTHOR INDEX
Abdelgadir, S. E, 25, 68 Argiolas, A., 44, 57, 66, 86, 88-90, 92,
Aberg, H., 42, 57 102
Acherman, A. E, 91 Arletti, R., 89, 103
Achermann, J. C., 23, 56, 67 Arnold, A. P, 77, 94, 99
Ackerman, A. E., 45, 56 Arnow, B. A., 29, 57
Ackman, D., 87, 100 Ashwell, K. W. S., 37, 64
Acuna-Castroviejo, D., 67 Asplund, R., 42, 57
Adachi, R, 90, 104 Aston-Jones, G., 81, 106
Adaikan, P. G., 84, 98 Athanassiou, K., 45, 64
Adkins-Regan, E., 16, 17, 18 Austin, C. P., 71, 106
Adler, N. T., 77, 91, 99, 110, 142 Azadzoi, K. M., 85, 92, 103, 104
Adson, D., 162, 166
Agyei.Y., 11, 18
Ahlenius, S., 84, 92, 96 Backensto, E. M., 114, 143
Airaksinen, J., 144 Backstrom, J. R., 92, 164
Akerlund, M., 45, 61 Bacon, J. P., 162, 167
Al-Attia, H. M., 47, 56 Bailey, J. M., 9, 11-14, 16, 18, 20, 23,
Albert, D. J., 29, 57 50, 51, 57
Aldasoro, M., 69 Bailey, J. N., 20
Alexander, C. J., 79, 105, 109, 144 Bailey, M., 50, 65, 68
Alexandre, L, 92, 97 Bakker, J., 54, 57
Alheid, G. R, 49, 63 Baldwin, P., 140
Allard, J., 86, 92, 97 Balesar, R., 33, 37, 43, 64, 65
Allen, L. S., 24, 31, 33, 37-39, 41, 49, Balkin, T. J., 121, 140
54,57 Balse-Srinivasan, P., 107
Aloi, J. A., 84, 92 Bancila, M., 83, 84, 92, 156, 164
Alster, P., 44, 71 Bancroft, J., 27, 57, 153, 164
Alterman, A. L, 162, 169 Band, L. C., 99
Alvarez, C., 48, 65 Bandler, R., 81, 92
Amagai, T., 99 Banner, L. L., 57
American Psychiatric Association, 148, Barfield, R. J., 83, 87, 90, 92, 101, 157,
164 167
American Spinal Injury Association, 140 Bari, M., 87, 105
Ames, M. A., 51, 60 Barnes, N. M., 84, 85, 92
Anderson, A. B. M., 45, 66 Barrington, F. J. F., 81, 93
Anderson, C., 14, 20, 50, 68 Bassford, T., 178
Anderson, C. H., 53, 57 Bafturk, M., 71
Anderson-Hunt, M., 43, 45, 57 Batch, J. A., 25, 57
Andersson, K.-E., 27, 66, 75, 76, 92 Bauer, H. G., 29, 58
Andersson, P. O., 45, 71 Baum, M. J., 27, 64, 67, 81, 83, 93, 137,
Andry, C., 103 145
Antelman, S. M., 81, 95 Bazzett, T. J., 86, 93, 107
Anthony, D. T., 169 Beach, F. A., 80, 93
Arai, Y., 83, 100 Beaudoin, G., 64
179
Beauregard, M., 64 Blumer, D., 151, 165
Becker, W., 123, 145 Bocklandt, S., 50, 60
Bednarek, M. A., 65 Boer, K., 60
Behbehani, M. M., 81, 93 Boer, R. C., 80, 98
Bell, A. P., 14, 15, 18, 23, 50, 57, 176, Bogaert, A. F., 15, 18
178 Bolton, N. J., 24, 58
Bell, C, 76, 93 Bonica, J. J., 110, 141
Bell, J. J, 66 Bonnefond, C., 37, 58
Benefield, C., 148, 168 Booth, A. M., 75-77, 96, 103
Benelli, A., 89, 103 Bornhovd, K., 138, 141
Benishay, D. S., 14, 18 Bors, E., 79, 94
Benoit, G., 62, 79, 93, 97 Bourgouin, P., 64
Benson, D. F., 28, 65 Bowen, D. J., 178
Bentele, K., 71 Bowser, R., 67
Berard, E. J. J., 109, 140 Boyd, H., 155, 169
Berendsen, H. H., 84, 90, 93, 107 Boyd, J., 69
Berger, B., 48, 65 Braak, E., 36, 37, 58, 69
Berglund, H., 43, 69 Braak, H., 31, 36, 37, 58, 69
Berkley, K. J., 77, 93, 110, 115, 140, 142 Brackett, N. L., 81, 94
Berkovitz, G. D., 72 Bradford, J., 153, 160, 165
Berlin, R, 150, 164 Bradley, S. J., 23, 47, 48, 58, 73
Bernabe, J., 79, 89, 92, 93, 97, /04 Bradley, W. E., 76, 104
Bernaschek, G., 63 Brady, K., 162, 169
Berthoud, H. R., 114, 141 Braun, A. R., 140
Bertolini, A., 89, 93, 103 Bredt, D. S., 76, 90, 94, 104
Bertrand, J., 46, 61 Breedlove, S. M., 77, 94, 99
Beyer, C., 53, 59, 140-J42 Brindley, G. S., 79, 88, 94
Bianca, R., 114, 140-/43 Brockhaus, H., 37, 58
Bieglmayer, C., 58, 141 Broekkamp, C. L., 84, 93
Biever, L. S., 150, 151, 166 Bromm, B., 141
Billerbeck, A. E. C., 59 Brown, B. D., 57
Bindert, A., 61 Brown, K., 62, 97
Bingham, R C., 59 Brown, R. L., 90, 96
Binstock, T., 15, 18 Brown, T., 65
Birder, L. A., 78, 93 Brown, T. R., 72
Birklein, F., 114, 142 Brown-Grant, K., 53, 58
Bitran, D., 83, 84, 87, 93, 99, 155, 164 Buchel, C., 141
Bjorklund, A., 83, 85, 86, 93, 100, 105 Bucy, P. C., 83, 99, 151, 167
Bjorkstrand, E., 44, 71 Buijs, R. M., 53,71, 86,94
Black, D. W., 160, 164 Burke, D., 51, 60
Blaicher, A. M., 44, 58, 141 Burnett, A. L, 76, 91, 94
Blaicher, W., 58, 116, 122, 138, 141 Burris, B. C., 155, 167
Blake, J., 73 Burton, S., 44, 67, 88, 103
Blanchard, R., 15, 18, 172, 178 Butler, P. C., 37, 58
Blanco, R., 104 Byne, W., 31, 37, 39, 41, 51, 54, 58, 59
Blaustein, J. D., 83, 106, 137, 144
Blessing, W. W., 37, 61
Blinn, K. A., 79, 94 Cador, M., 83, 96
Bloch, G. J., 37, 58 Cadore, L. P., 44, 62
Blok, B. F., 84, 107 Caggiula, A. R., 81, 95
Blomqvist, A., 45, 66 Galas, A., 82, 106
180 AUTHOR INDEX

Calligaro, D. O., 97 Clouet, D., 157, 169
Campbell, B., 44, 59 Cohen, R. M., 69
Candemir, Z., 71 Cohen-Kettenis, P. T., 23, 59, 60
Canning, D. A., 48, 72 Colapinto, J., 47, 59
Card, J. P., 78, 94 Cole, T., 109, 141
Carey, M. P., 88, 94 Cole-Harding, S., 23, 51, 60
Carlson, R. R., 77, 94 Coleman, E., 147-149, 152, 157, 160-
Carlsson, A., 92 162, 165, 166, 168
Carlsson, C. A., 79, 96, 100 Collado, P., 53, 59
Carmichael, M. S., 44, 45, 59, 88, 94, Collins, J. J., 114, 141
116, 122, 138, 141 Comarr, A. E., 79, 94
Carr, M. C., 48, 72 Condra, M., 88, 103, 104
Carro-Juarez, M., 84, 95 Coolen, L. M., 79, 83, 95, 106, 137, 144
Carson, C., 88, 98 Coolidge, F. L., 23, 46, 59
Carson, S., 172, 178 Copelin, T., 78, 103
Carter, C. S., 44, 59, 89, 95 Cordier, B., 162, 169
Carter, L. S., 43, 59 Correa, R. V., 23, 59
Carter, R. A., 178 Courtney, K., 27, 62
Casey, K. L, 138, HI Courtois, F., 62, 97
Cavazzuti, E., 89, 103 Courty, E., 86, 95
Cechetto, D. R, 82, 95 Courty, P., 86, 95
Cerruti, C., 84, 101 Cowan, W. M., 82, 104
Cervantes, M., 87, 98 Criminale, C., 142
Cesnik, J., 149, 161, 165 Cristiane, L., 71
Chambers, K. C., 86, 95 Cross, B. A., 27, 60, 122, 138, 141
Chan, J. Y. H., 83, 95 Crowley, T. J., 90, 95, 158, 165
Chan, S. H. H., 82, 95 Cueva-Rolon, R., 114, 140-143
Chang, L. S., 83, 95 Cummings, J. L., 27, 28, 62, 65, 66, 149,
Chang, T. S., 94 151, 167, 168
Chang, T. S. H., 76, 94 Cunningham, S. T., 110, 141
Charney, P., 178 Curran, T., 78, 104
Chawla, M. K., 37, 59 Cushman, P., 90, 95, 158, 165
Checkley, S. A., 44, 45, 67, 88, 103
Chen, K. K., 82, 95
Chen, K.-K., 44, 59 Dahl, E., 17, 19
Chernick, A. B., 47, 58 Dalle Ore, G., 28, 70
Cherny, S., 19, 63 Dalm, E., 81, 98
Chien, P. Y., 51, 61 Damasio, A. R., 150, 165
Chivers, M. L., 9, 20 Damasio, H., 150, 165
Cho, J. K., 144 Dammann, O., 71
Choate, J. V. A., 68 Damsma, G., 137, 144
Chow, T., 151, 167 Davidson, J. M., 44, 59, 82, 87, 94, 95,
Christ, G. J., 104 116, 141
Christenson, G. A., 160, 168 Davidson,]. R. T., 160, 165
Chung, S. K., 80, 101 Davidson, R. J., 156, 166
Chung, W. C. J., 24, 59 Davies, H. R., 57
Clancy, A. N., 81, 98 Davis, B. L, 77, 87, 95
Clark, J. T., 87, 95 Davis, P. G., 91
Clark, T. K., 81, 95 Dawood, K., 18, 57
Clattenburg, R. E., 53, 59 Dawson, T. M., 104
Clemens, L. G., 45,56, 82, 88,91, 95, 107 Deecher, D. C., 67
AUTHOR INDEX 181

De Feo, V. J., 77, 94 Ebers, G., 14, 20, 27, 66, 68, 149, 167
de Groat, W. C., 75, 78, 79, 81, 84, 85, Eckersell, C., 37, 58
93, 96, 105 Edgar, M. A., 58
De Jonge, F. H., 36, 60 Edwards, D. A., 28, 60, 81, 94, 98
DeLamater, J. D., 11, 19 Ehlhart, T, 54, 70
Dellovade, T. L., 49, 66 Ehrhardt, A. A., 22, 23, 50, 60, 66
De Muinck Keizer-Schram, S. M. P. F., 69 Eippers, B. A., 89, 100
Dennerstein, L., 43, 45, 57 Elliot, M. L, 150, 151, 166
De Olmos, J., 49, 63 Ellis, L, 16, 19, 23, 51, 60
DePalma, R. L, 80, 102, 156, 167 Emmons, S. W., 16, 19, 172, 178
Derdinger, F., 92 Endert, E., 36, 60, 71
Desmond, J. E., 57 Endo, A., 26, 72
Dessens, A. B., 23, 26, 46, 60 Enquist, L. W., 94
Devlieger, H., 22, 60 Erdman, W. J., II., 79, 104
De Vries, G. J., 24, 59 Erhardt, A. A., 47, 67
De Wall, H., 81, 98 Ericson, H., 45, 66
De Wied, D., 71 Erlandson, B. E., 79, 96, 100
Dewing, P., 26, 60 Ernst, E., 88, 96
De Zegher, F., 22, 60 Erskine, M. S., 83, 96, 100, 137, 142,
Diamond, L. E., 27, 47, 67 144, 145
Diamond, M., 12, 20, 23, 60 Escalante, A. L., 84, 96
Dickey, R., 162, 166, 172, 178 Esel, E., 71
Dieckmann, G., 29, 60 Espila, A. M., 37, 64, 65
Ding, Y. Q., 110, 141 Etienne, P., 87, 100
Dittmann, R. W., 23, 50, 60 Evans, B. A. J., 57
Dixen, J., 44, 59, 116, 141 Everitt, B. J., 81-83, 86, 90, 93, 96, 99
Dixon, J., 94 Evers, P., 60
Doherty, P. C., 84, 98 Exton, M. S., 27, 61
Domenech, C., 69
Domenice, S., 59
Domer, F. R., 90, 96 Fabbri, A., 90, 96
Dominguez, J., 101 Facchinetti, P., 82, 106
Donker, P. J., 76, 107 Fagerstrom, R. M., 46, 61
Dorner, G., 39, 60 Fakhrai, A., 23, 46, 69
Dorr, R., 90, 107 Fall, M., 79, 96, 100
Downie, J. W., 78, 96 Fallen, B. A., 169
Drop, M. D., 69 Farrer, L. A., 18, 57
Droupy, S., 97 Faught, R. E., 114, 143
Du, H.-J., 80, 85, 96 Federoff, J. P., 157, 160, 166
Du, J., 99 Fedirchuk, B., 78, 96
Dun, N. J., 91, 96 Feiger, A., 161, 166
Dun, S. L., 96 Feldman, J. F., 60
Diindar, M., 71 Felten, D. L, 110, 127, 134, 138, 142
Dunne, M. P., 12, 18 Ferguson, J. K. W., 138, 142
DuPree, M. G., 50, 60 Femandez-Guasti, A., 37, 39-42, 49, 61,
Durif, F., 86, 95 65, 84, 87, 96, 104
Dwyer, S. M., 149, 165 Ferrari, W., 89, 93, 97
Ferrini, M. G., 90, 97
Fibiger, H. C., 137, 144
Earle, D., 27, 67 Fillingim, R., 114, 143
Eaton, R. C., 93, 99, 107 Finkelstein, J. W., 66
182 AUTHOR INDEX

Finn, P. D., 27, 72 Gebhard, P. H., 10, 19
Fisher, C, 25, 67 Gebhart, G. F., 114, 144
Fitzgerald, J. A., 68 Geffen, L. B., 37, 61
Fleming, S., 73 Gehm, B. D., 51, 61
Fletcher, T. F., 76, 104 Georgiadis, J. R., 142
Fliers, E, 27, 30, 36, 37, 54, 61, 62, 69 Gerdes, C., 115, 139, 143, 145
Flumerfelt, D. L, 160, 164 Gerdes, C. A., 77, 100, 109, 111-115,
Foa, E. B., 160, 168 139, 142-144
Fodor, M., 37, 40, 42, 61, 65 Gerhardt, C. C., 84, 97
Fong, T. M., 65 Gerlaugh, R. L, 79, 104
Foreman, M. M., 84-86, 97 Gessa, G. L., 44, 57, 86, 89, 90, 92, 93,
Forest, M. G., 22, 24, 46, 61 97, 102, 155, 166
Forsermann, U., 96 Getzinger, M. J., 83, 106, 137, 144
Forsling, M. L, 45, 61, 64 Gibbs, R. B., 54, 68
Frank, G. R., 69 Oilman, S. E., 13, 19
Frankel, M., 28, 65 Ginton, A., 34, 66, 82, 102
Frankhuijsen-Sierevogel, A. C., 71 Giovenardi, M., 44, 62
Franzese, A., 96 Giuliano, F., 36, 62, 78, 79, 82, 86, 89,
Frayne, J., 45, 61 92, 93, 97, 104, 106
Freund-Mercier, M.-J., 106 Gladue, B. A., 39, 62
Frohman, E. M., 27, 61, 149, 166 Glauche, V., 141
Frohman, T., 149, 166 Glover, G. H., 57
Frohman, T. C., 27, 61 Glover, T. D., 27, 60
Fuciarelli, K., 107 Gnessi, L., 96
Fukai, K., 81, 97 Goekoop, J. G., 71
Fukuda, H, 81, 97 Goetz, C. G., 106
Fulker, D., 19 Gold, M. S., 87, 102
Fulker, D. W., 63 Goldstein, A., 85, 90, 97
Fuller, R. W., 97 Goldstein, I., 88, 92, 97, 98, 103
Fuller, S. A., 144 Goldstein, J. A., 90, 98
Futreal, P. A., 19 Golombok, S., 23, 51, 62
Futterweit, W., 23, 46, 61 Gomez, L. E., 140-142
Fuxe, K., 86, 96 Gomora, P., 142
Gonzales-Cadavid, N. F., 90, 97
Gonzales-Mariscal, G., 142
Gabard, D. L., 17, 19 Goodwin, F. K., 87, 98
Gagnon, J. H., 10, 19 Gooren, L. J. G., 22, 23, 27, 31, 35, 49,
Gai, W. P., 37, 61 50, 55, 59, 62, 65, 70
Gajdusek, D. C., 63 Gores, T., 48, 72
Ganduglia-Pirovano, M., 140, 142 Gordon, J. H., 30, 62
Gao, B., 37, 61 Gorman, D. G., 28, 62
Garcia, M. M., 49, 63 Gorski, R. A., 24, 30, 31, 33, 37, 54, 57,
Garcia-Bazan, M., 143 62,69
Garman, C., 142 Gorzalka, B. B., 84, 90, 98, 103
Garrels, L., 46, 61 Goscinski, I., 151, 166
Garrick, N. A., 84, 106 Goto, Y., 82, 107
Caspar, P., 48, 65 Gottfries, C. G., 33, 62
Gaus, S. E., 36, 37, 61 Gouras, G. K., 49, 62
Gautier, T., 25, 63 Gower, A. J., 90, 93
Gavey, N., 177, 178 Goy, R. W., 82, 105
Gearhart, J. P., 23, 48, 68, 72 Grace, V., 177, 178
AUTHOR INDEX 183

Grant, J. E, 162, 166, 168 Hartmann, U., 61
Gratzer, T., 160, 161, 165 Hasson, H. M., 76, 98
Greco, B., 81, 98 Hayashida, M., 162, 169
Green, R., 23, 39, 46, 51, 62 Hayes, E. S., 84, 98
Greenberg, M., 155, 169 Haynes, P. J., 45, 66
Greenleaf, W., 59, 94, 141 Heath, R. G., 28, 63
Griffin, J. E., 25, 72 Heaton, J. P., 87, 98
Griffiths, D., 81, 98 Hedlund, P., 27, 66
Griffiths, S., 155, 167 Heeb, M. M., 137, 144
Grimes, S., 143 Heimann, H., 29, 63
Grade, M., 27, 66, 149, 167 Heimer, L., 49, 63
Gross, J., 138, 144 Helke, C. J., 84, 106
Gruber, D., 58, 141 Helleman, R. E., 39, 62
Gruen, R. S., 66 Hendricks, S. E., 80, 107, 108
Grumbach, M. M., 25, 67 HengstschlSger, M., 23, 63
Guan, X., 65, 106 Hepner, B. C, 84, 104
Guevara, M. A., 87, 98 Herbert, J., 90, 99
Guevara-Guzman, R., 143 Herman, R. A., 138, 142
Guldner, F.-H., 53, 62 Hernandez-Gonzales, M., 87, 98
Gulyas, B., 43, 69 Hertz, R., 172, 178
Gutierrez, G. M., 37, 59 Heston, L, 11, 19
Gwinup, G., 88, 98 Higuchi, T., 63
Hillegaart V, 84, 96
Hines, M., 24, 31, 57
Hackett, J., 107 Hinkin, C. H., 151, 167
Hadley, M. E, 90, 107 Hiort, O., 21, 63
Hall, J. L, 86, 97 Hjorth, S., 92
Hamann, S. B., 138, 142 Hoffman, N. W., 27, 53, 72
Hamburger-Bar, R., 86, 98 Hoffmann, R. G., 144
Hamer, D., 14, 19 Hofman, M. A., 22, 24, 27, 30, 31, 33-
Hamer, D. H., 23, 50, 60, 62, 63 36, 38, 39, 42, 49-51, 54, 55,
Hampson, J. G., 47, 67 63-65, 70, 72, 172, 178
Hampson, J. L, 47, 67 Hoglund, U., 45, 66
Han, A G., 107 Hokfelt, F. T., 86, 96
Hancock, M. B., 76, 98 Hollander, E., 169
Handwerker, H. O., 114, 142 Holman, S. D., 53, 59, 63
Hanley, D. R, 94 Holmes, G. M., 99
Hanrahan, S. B., 137, 142 Holstege, G., 80, 81, 84, 98, 107
Hansen, J., 107 Holstege, J. C., 80, 98
Hansen, S., 84, 105 Honda, C. N., 78, 82, 99
Hanson, L. A., 84, 98 Honda, K., 43, 63, 107
Hansteen, R. W., 90, 97 Honnebier, M. B. O. M., 51, 70
Harada, N., 22, 69 Hood, J., 73
Haraguchi, N., 70 Horita, H., 90, 104
Hardjasudarma, M., 151, 168 Horvath, S., 26, 53, 60
Harkness, B., 143 Horvath, T. L., 71
Harlan, R. E, 49, 63 Hostege, G., 137, 142
Harris, C, 104 Hotta,H., 110, 140
Harsch, H. H., 144 Howard, A. D., 65, 71, 106
Harshman, K., 19 Howard, G., 38, 63
Hart, B. L., 82, 98, 105 Hruby, V., 90, 107
184 AUTHOR INDEX

Hu,N., 14, 19, 50,63,65 Ju, G., 141
Hu, S., 14, 19, 23, 50, 63, 65 Julien, E., 87, 99
Hiiber, J. C., 58, 63, 141
Hubscher, C. H., 80, 99, 115, 142
Hughes, A. M., 90, 99 Kafka, M. P., 157, 160, 166
Hughes, H. E., 48, 73 Kahl, U., 67
Hughes, I. A., 57 Kalin, N. H., 156, 166
Hull, E. M., 83-87, 93, 99, 101, 103, Kallmann, R J., 11, 19, 64
107, 155, 164 Kalnin, A., 142, 143
Hulse, C., 142 Kalra, P. S., 87, 95
Humbert, R., 59, 94, 141 Kalra, S. P., 95
Hutchinson, J., 77, 99 Kalsbeek, A., 54, 65
Hutchison,]., 110, 142 Kamphorst, W., 70
Hutchison, J. B., 53, 59, 63 Kanouse, D. E., 10, 19, 172, 178
Huws, R., 151, 166 Kappes, M. E., 50, 60
Hwang, P. M., 90, 94 Kappes, M. H., 50, 60
Hyde, J. R, 38, 63 Karakiulakis, G., 53, 65
Hyde.J. S., 11, 19 Karama, S., 27, 64
Kartha, K. N. B., 36, 64
Katholi, C. R., 80, 102, 156, 167
ladarola, M. J., 78, 93 Katz, L.S., 16, 20
lannucci, U., 89, 90, 102 Kawano, H., 69
Imanishi, J., 99 Kehrberg, L. L., 160, 164
Imperato-McGinley, J., 23, 25, 63 Kellner, R., 153, 168
Insel, R. T, 144 Kemether, E., 58
Insel, T. R., 43, 64, 72, 84, 92 Kendler, K. S., 13, 19
Ishunina, T. A., 33, 42, 43, 64 Kessler, R. C, 13, 19
Islam, A., 88, 98 Kettl, P., 109, 142
Itabashi, H., 151, 168 Keverne, E. B., 23, 46, 62
luvone, P. M., 81, 94 Keyes, J. W., Jr., 143
Khantzian, E. J., 157, 166
Kidd, G. J., 104
Jackson, D. C., 156, 166 Kiely, M. E., 87, 100
Jacoby, KM 142 Kiev, A., 161, 166
Jameson, J. L., 23, 51, 56, 61, 67 Kim, S. W., 162, 166, 168
Janig, W., 76, 99 Kindon, H. A., 27, 36, 64
Jannini, E. A., 96 King, M. N., 12, 19
Jardin, A., 62, 97 King, V. L., 65
Jeffries, K., 140 Kinsey, A. C., 10, 15, 19
Jenck, R, 84, 93 Kinzie, J., 162, 167
Johansson, C., 45, 66 Kirchner, A., 114, 142
Johnson, B. T., 88, 94 Kirkpatrick, M., 51, 64
Johnson, R. D., 80, 99 Kissler, S., 123, 145
Johnson, V. E., 143 Klassen, P., 15, 18
Jones, C. L, 172, 178 Klawans, H. L., 106
Jonk, R. H., 29, 57 Klein, D. R, 169
Jonsson, C., 86, 96 Kleopoulos, S. P., 54, 68
Jordan, C. L., 77, 99 Kluver, H., 99, 151, 167
Jornvall, H., 37, 70 Knogler, W., 58, 141
Joubert, S., 64 Kockott, G., 61
Jozefbwicz, R. R, 110, 127, 138, 142 Kodman-Jones, C., 48, 72
AUTHOR INDEX 185

Kohlert, J. G., 37, 58 Laryea, E., 100
Koivisto, M., 24, 58 Lasco, M. S., 58
Kojima, M., 81, 99 Laumann, E. O., 10, 11, 19
Kolarsky, A., 151, 167 Lavarenne, J., 86, 95
Kolb, L. C., 154, 155, 167 Lavielle, G., 84, 102
Koliatsos, V. E., 49, 62 Lawrence, B., 66
Kollar, E. J., 77, 99 Laws, D. R., 153, 168
Komisaruk, B., 77, 91, 99, 100, 107, Le Blond, C. B., 53, 65
109-116, 119, 124, 137-140, Lecoq, A., 46, 61
141-145 LeDoux, J., 154, 167
Kondo, Y., 83, 100 Lee, B.-H., 94
Koppe, J. G., 60 Lee, E.-J., 23, 56
Kordower, J. H., 67 Lee, H., 151, 168
Kostoglou-Athanassiou, I., 45, 64 Lee, J. W., 78, 100
Koutcherov, Y., 37, 64 Leedy, M. G., 82, 98
Kovenock, J., 24, 71 Leiblum, S. R, 177, 178
Kow, L. M., 110, 143 Lemer, A. M., 151, 168
Kow, L-M., 77, 100 Leroux, J.-M, 64
Kraan, E., 42, 65 Lesur, A., 49, 65
Kraft, C., 162, 168 LeVay, S., 31, 37, 39, 41, 54, 65
Krane, R. J, 85, 92, 103 Lever,]., 10, 19, 172, 178
Kristal, M. B., 110, 144 Levine, N., 90, 107
Kriiger, T., 61 Lewis, V. G., 50, 67
Kruijver, F. P., 33, 37, 39, 40-42, 43, 49, Li, J. L, 141
50,55,61,64,65 Li, L, 19, 63
Krystal, J., 155, 169 Liang, P., 28, 60
Kuhn, J. M., 162, 169 Licht, P., 123, 145
Kuikka, J., 144 Liebowitz, M. R., 169
Kupila, J, 144 Lightman, S. L., 44, 45, 67, 88, 103
Kurohata, T., 90, 104 Lilly, R., 28, 65
Kuru, M., 81, 100 Lin, C. E., 114, 141
Kuwabara, Y., 44, 70 Lindberg, P., 92
Kuypers, H. G. J. M., 78, 80, 88, 98, Lindblom, J., 107
100, 106 Lindstrom, S., 79, 100
Kwee, I. L., 151, 168 Lindvall, O., 85, 86, 93, 100, 105
Kwiatkowski, S., 151, 166 Ling, N., 89, 100
Lipton, J., 16, 19, 172, 178
List, M. S., 80, 101
Lahr, G., 26, 66 Liu, W.-C., 142, 143
Lake Polan, M., 57 Liu, Y.-C., 27, 43, 48, 49, 65
Lakhdar-Ghazal, N., 54, 65 Lizza, E. F., 88, 107, 108
Lai, S., 87, 100 Lluch, S., 69
Lamarz, M., 151, 168 Loewy, A. D., 80-83, 100, 104
Landen, M., 46, 65 Longueville, F., 89, 97
Lane, R. M., 80, 84, 85, 100, 156, 167 Lookingland, K. J., 87, 95
Lange, G. M., 45, 56, 91 Lorenz, J., 138, 141
Langevin, R., 150, 167 Lorrain, D. S., 85, 86, 99, 101
Langworthy, O. R., 76, 100 Loucks, J. A., 99, 107
Lanta, L., 48, 72 Louwerse, A. L., 36, 60, 71
Larkin, K., 28, 68 Lowenstein, C. J., 76, 94
Larsson, K., 82, 84, 92, 96, 106 Luby, E. D., 162, 167
186 AUTHOR INDEX

Lucion, A. B., 44, 62 McCurdy, J. R., 103
Lumley, L. A., 93, 99 McDonald, E., 12, 19
Lundstrom, B., 46, 65 McDonald, P. G., 81, 92
Lynn, R. B., 94 McDonald, T. J., 37, 70
McEwen, B. S., 60
McFarlane, A. C., 160, 169
Mack.J. E., 157, 166 Mclntosh, T. K., 83, 87, 90, 101, 167
Macke, J. P., 25, 65 Mclntyre, H., 27, 66, 149, 167
MacLean, P. D., 27, 29, 34, 41, 43, 65 McKellar, S., 80, 81, 83, 100
MacNeil, D. J., 27, 65 McKenna, K., 27, 34, 36, 43, 44, 66, 76-
Madlafousek, J., 151, 167 84, 88, 92, 97, 101-103, 156,
Magee, T. R., 90, 97 164, 167, 173, 178
Magnuson, V., 14, 19 McLachlan, EM., 76, 99
Magnuson, V. L., 50, 63 McMullen, N. T., 37, 59, 68
Maguire, M. P., 94 Me Vary, K. T., 80, 101
Mai, J. K., 37, 48, 64, 72 Meade, R. P., 94
Mains, R. E, 89, 100 Medina, P., 69
Maixner, W., 114, 143 Meeks, J. J., 23, 56
Mallory, B., 79, 105 Meiners, L. C., 142
Malsbury, C. W., 82, 101 Meisel, R. L., 82, 102
Mancall, E L., 28, 66 Melis, M. R., 44,57, 66, 86, 88-90, 92,
Mandrika, L, 107 102
Manzanares, J., 87, 95 Mellenbergh, G. J., 60
Markowski, V. P., 93,99, 107 Mello, N. K., 153, 167
Marlier, L., 84, 101 Mendelson, J. H., 153, 167
Marlowe, W. B., 28, 66 Mendez, M. R, 151, 167
Marrazzi, M. A., 162, 167 Mendonca, B. B., 59
Marshall, E., 9, 19 Mengod, G., 37, 58
Marson, L., 78, 80-84, 88, 101, 103, Merari, A., 34, 66, 82, 102
106, 156, 167 Mesulam, M. M., 151, 167
Martin, C. E., 10, 19 Meyer, W. J., 46, 66
Martin, G. R, 80, 101 Meyer-Bahlburg, H. R L, 22, 23, 46, 50,
Martin, J., 12, 20 60, 66, 72
Martin, L. J., 49, 66 Meyers, R., 28, 66
Martin, N. G., 12, 18 Meyerson, B. J., 45, 66
Martin, W. J., 71, 106 Michael, N., 61
Martinez-Leon, J. B., 69 Michael, R. P., 81, 98
Martin-Garcfa, J. A., 67 Michael, R. T., 10, 19
Marton, E., 63 Michaels, S., 10, 19
Mash, D. C., 67 Migeon, C. J., 72
Masters, W. H., 143 Miki, Y., 9, 19
Matsumoto, T., 69 Millan, M. J., 84, 102
Matsuura, T., 99 Miller, B., 149-151, 167
Matthews, A., 90, 96 Miller, B. L, 27, 28, 66, 151, 168
Matuszewich, L., 84-86, 99, 101 Miller, E., 151, 168
Mayer, A., 26, 66 Miller, K. E., 78, 103
Mayer, A. D., 110, 141 Miller, M., 63
Mayer, B., 103 Miller, M. B., 18, 57
McAndrews, J. M., 51, 61 Miller, N. S., 87, 102
McBean, A., 147, 165 Mills, R., 37, 58
McConnel, R. A., 81, 95 Miner, M., 148, 160, 168
AUTHOR INDEX 187

Minoshima, S., 138, 141 Nagura, H., 22, 69
Miselis, R. R., 94 Nair, N. P., 100
Mitchell, M. D., 45, 66 Nakach, N., 27, 68
Mizuno, M., 44, 70 Nakada, T., 151, 168
Mizusawa, H., 27, 66 Nakano, Y., 16, 20
Mobbs, C. V., 54, 68 Nargund, R. P., 65, 71, 106
Modell, J. D., 80, 102, 156, J67 Narita, K., 63
Modell, J. G., 84, 85, 102, 156, 167 Neale, M. C., 11, 18
Molenaar, J. C., 69 Negoro, H., 63,82, 107
Molin-Carballo, A., 54, 67 Negrete, J., 100
Molinoff, P. B., 27, 67 Nelson, D. L., 97
Money, J., 23, 46, 47, 50, 67, 72, 149, Nescvacil, L, 161, 165
151, 157, 162, 168 Ness, T.J., 114, 143
Monga, M., 151, 168 Neuwalder, H. F., 66
Monga, T. N., 168 New, M. I., 66
Monsma, F. J., 85, 103 Nicholson, H. D., 45, 61
Montemurro, D. G., 53, 59 Nickolaus, S., 84, 106
Moore, A., 149, 165 Nievergelt, C., 50, 60
Moore, K. E., 87, 95 Ninomiya-Alarcon, J. G., 143
Moore, R. Y., 37, 61 Nobin, A., 85, 93
Morales, A., 88, 103, 104 Nolan, C. L, 138, 142
Morali, G., 87, 98 Noppen, N. W. A. M., 37, 61
Moreault, A. M., 61, 149, 166 Norgren, R., 124, 144
Moretti, C., 96 Novotna, V., 151, 167
Morgello, S., 58 Nygren, L. G., 81, 103
Morishima, A., 25, 66, 67
Morris, N. M., 24, 53, 71
Morris, S., 65
Morrow, T. J., 138, 141 O'Brien, C. P., 169
Moses, J., 99 Ochoa, B., 47, 67
Mosier, K., 143 Ohfu, M., 42, 70
Mosier, K. M., 124, 142 Ohlerking, F., 160, 168
Muceniece, R., 107 Okada, H., 81, 97
Mueller, E. A., 84, 92 Okazaki, M., 42, 70
Mufson, E. J., 49, 67 Oliver, G., 47, 73
Miiller, D., 29, 67 Oliver, G. D., 58
Muhamaki, S., 68 Olivier, B., 84, 107
Munoz-Hoyos, A., 67 Olson, L, 81, 103
Murata, T., 63 Ono, H., 42, 70
Murgia, S., 89, 92 Ooms, M. P., 60
Murphy, D. L, 84, 88, 92, 106 Orlowiejska, M., 151, 166
Murphy, J. J., 79, 104 Oropeza, M. V., 87, 98
Murphy, M. R., 44,45, 67, 103, 157,168 Ortega-Villalobos, M., 114, 143
Murphy, R. L, 18, 57 Ortego, N., 151, 168
Mustanski, B. S., 9, 20, 50, 60 Orthner, H., 29, 67
Mutalipassi, L. R., 154, 167 Ottenweller, J. E., 144
Mutt, V., 37, 70 Over, R., 87, 99
Owen, J., 88, 104
Owen, J. A., 103
Nadelhaft, L, 76, 77, 79, 101-103 Ozisik, G., 23, 67
Nadig, P. W., 104 Ozkul, Y., 71
188 AUTHOR INDEX

Paans, A. M. J., 142 Pomerantz, S. M., 84, 104
Padoin, M. J., 44, 62 Pomeroy, W. B., 10, 19
Palacios, J. M., 37, 58 Pool, C. W., 55, 65
Palmisano, G., 59, 94, 141 Post, C, 107
Pankiewicz, J., 144 Potts, A., 177, 178
Papka, R. E., 78, 83, 103, 114, 141 Powell, R., 53, 65
Paredes, R. G., 27, 36, 67, 68 Powers, R. E., 49, 66
Parades, R. J., 27, 64 Prendergast, M. A., 80, 107, 108
Park, K., 76, 103 Prentky, R., 160, 166
Parker, K. L, 59 Preuss, W., 61
Parker, R. A., 36, 61 Price, D. L., 49, 66
Parks, C., 51, 57 Price, E. O., 16, 20
Partanen, K., 144 Privat, A., 84, 101, 104
Partiman, T. S., 54, 69 Probst, A., 37, 58
Partyk, A., 151, 166 Prusis, P., 107
Pattatucci, A., 19, 50, 63 Punnonen, R., 45, 68
Patterson, C., 19, 63 Purba, J. S., 70
Patterson, M. N., 57 Puri, P., 78, 103
Paxinos, G., 37, 64 Purinton, P. T., 76, 104
Payton, T., 85, 92 Putnam, S. K., 101
Pearce, J., 151, 168
Pearson, B., 51, 59
Peckham, W., 51, 60 Qin, K., 25, 67
Peglion, J. L, 84, 102 Quante, M., 141
Pehek, E. A., 86, 99, 103 Quigley, A., 22, 25, 68
Peng, L., 38, 63 Quon, C. Y., 27, 67
Perkins, A., 68
Perrin-Monneyron, S., 84, 102
Peters, H. J. P. W., 83, 95 Raadsheer, F. C., 70
Peters, L. C., 110, 144 Rada, R., 153, 168
Petersen, W. E., 44, 59 Rada, R. T., 153, 168
Peterson, R. E., 25, 63 Raifer, J., 90, 97
Petersson, M., 44, 71 Raina, M. S., 151, 168
Pevet, P., 54, 65 Rainey, W. E., 59
Peveto, C. A., 76, 98 Raisman, G., 53, 58
Pfaff, D. W., 54, 68, 77, 100, 110, 143 Rajput, A. H., 106
Pfaus, J. G., 54, 68, 90, 103, 137, 144 Ramakrishna, T., 36, 64
Phoenix, C. H., 86, 95 Rampin, O., 78, 79, 82, 89, 92, 93, 97,
Pieribone, V. A., 81, 106 104, 106, 164
Pilgrim, C., 26, 27, 66, 68 Ramping, O., 62
Pillard, R. C, 9, 11, 13, 16, 18, 20, 57, Ranee, N. E., 37, 49, 59, 62, 68
68 Randich, A., 114, 143, 144
Ptlleri, G., 29, 68 Rasmussen, K., 97
Pittard, J. T., 104 Rattner, W. H., 79, 104
Pittler, M. H., 88, 96 Ravid, R., 70
Platt, K. B., 78, 101, 103 Raymond, N., 147, 148, 160, 161, 162,
Ploner, M., 138, 144 165, 168
Ploog, D. W., 27, 29, 34, 41, 43, 65 Reid, K., 88, 104
Poeck, K., 29, 68 Reinders, A. A. T. S., 142
Poggioli, R., 89, 103 Reiner, W. G., 23, 48, 68
Polak, J., 151, 166 Reisert, I., 26, 27, 66, 68
AUTHOR INDEX 189

Renter, K., 61 Saper, C. B., 36, 61, 81, 82, 95, 100,
Repa, C., 63 104
Resko, J. A., 25, 28, 68, 69 Sar, M., 82, 104
Rice, G., 14, 20, 23, 68 Sasano, H., 22, 69
Richards, E., 77, 107, 139, 144 Sato, T., 25, 69
Ridet, J. L, 84, 104 Sato, Y., 77, 90, 93, 104, 110, 140
Rieber, L, 29, 68 Satoh, F., 22, 69
Rigter, H., 86, 98 Savic, I., 43, 69
Rinamam, L., 94 Sawchenko, P. E., 87, 88, 105
Ringman, J., 151, 167 Sayag, N., 27, 72
Risch, N., 14, 20, 68 Schatzberg, A. F., 157, 166
Rittberg, B., 162, 168 Schedlowski, M., 61
Robbins, A., 77,93, 110, 140 Scheller, F., 61
Robbins, T. W., 83, 96 Schioth, H. B., 89, 92
Robinson, B. E., 162, 168 Schlosser, S. S., 160, 164
Roch Lecours, A., 64 Schmidt, G., 29, 61, 69
Rodriguez-Cabezas, T., 67 Schmidt, H. H., 85, 96
Rodriguez-Manzo, G., 84, 87, 95, Schmidt, R. H., 105
104 Schneider, H., 29, 60
Roeder, F., 29, 67 Schneider-Jonietz, B., 29, 60
Rogers, W. R, 10, 19, 172, 178 Schneier, F. R., 169
Rokaeus, A., 37, 70 Schnitzler, A., 138, 144
Roland, P., 43, 69 Schorsch, E., 29, 69
Roos, B. E., 33, 62 Schr0der, H. D., 77, 81, 87, 105
Roppolo, J. R., 78, 93 Schultz, C., 31, 69
Rose, J. D., 81, 82, 104 Schwartz, M., 50, 67
Roselli, C. E., 25, 28, 68, 69 Scott Young, W., Ill, 37, 49, 59, 62
Rosen, L. R., 60, 66 Seckl, J. R., 44, 45, 67, 88, 103
Rosen, R., 79, 88, 98, 105, 109, 144 Segarra, G., 42, 44, 69
Rothbaum, B. O., 160, 168 Segraves, K., 87, 105
Rowe, D. W., 137, 144 Segraves, R. T., 87, 105
Rowley, F., 142 Sekine, K., 69
Roy, R., 51, 64 Shackleton, C., 63
Rubey, R., 162, 169 Shadiack, A. M., 27, 67
Russell, D. W., 25, 72 Sharp, F. R., 78, 104
Rustioni, A., 91, 106 Sharp, T., 84, 85, 92
Rutter, M, 51, 62 Shattuck-Eidens, D., 19
Shefchyk, S. J., 78, 96
Shen, Y., 85, 103
Sachs, B. D., 27, 65, 82, 102 Shi, J., 141
Sadeghi, M., 23, 46, 69 Shi, T., 26, 60
Saeger, W., 71 Shields,]., 11, 19
Saenz de Tejada, I., 85, 104 Shimokochi, M., 81, 105
Sagar, S. M., 78, 104 Shimshi, M., 66
Saito, S., 91, 94, 104 Shimura, T., 81, 105
Salamone, J. D., 27, 65 Shin, Y. C., 162, 166
Salehi, A., 42, 43, 64 Shinwari, A., 58
Salle, B., 46, 61 Shipley, M. T., 81, 92
Sanders-Bush, E., 92, 164 Shoji, Y., 70
Sano, Y., 99 Shrivastava, R. K., 161, 166
Sansone, G., 123, 140-143, 144 Shryne.J. E., 24, 30, 31,57, 62
190 AUTHOR INDEX

Shubsachs, A. P., 151, 166 Succu, S., 44, 66, 89, 90, 102
Sigmundson, K., 23, 47, 60 Suchindran, C., 22, 71
Sigusch, V., 29, 68 Surridge, D. H., 104
Simerly, R. B.( 37, 69, 81, 82, 105 Suzuki, N., 104
Simpson, A., 90, 95, 158, 165 Svensson, L, 84, 92, 105
Simpson, E. R., 25, 67 Swaab, D. F., 22, 24, 26, 27, 29-31, 33-
Singh, R. P., 53, 59 40,42,43,49-51,53-55,59,61,
Sipski, M. L, 79, 105, 109, 135, 144 63-66, 69-72, 172, 178
Siroky, M. B., 103 Swanson, L. W., 37, 69, 81, 82, 87, 88,
Sjogren, C, 45, 71 104-106
Skagerberg, G., 81, 83, 85-87, 100, 105 Swensen, J., 19
Skottner, A., 107 Szele, F. G., 84, 106
Skuse, D. H., 26, 69
Slijper, F. M. E., 23, 46, 69
Slimp, J. C., 82, 105 Tagliamonte, A., 155, 166
Slob, A. K., 54, 57 Takada, G., 70
Smith, C., 51, 64 Takahashi, H., 69
Smith, E. P., 25, 69 Takahashi, I., 70
Smith, E. R., 87, 95 Takahashi, K., 22, 69
Snyder, HMcC., 48, 72 Takahashi, T., 22, 70
Snyder, S. H., 76, 90, 94 Takano, K., 42, 70
Sofuoglu, S., 71 Takeda, S., 44, 70
Sohlstrom, A., 44, 71 Tamir, H., 84, 104
Solano-Flores, L. P., 143 Tanaka, A., 99
Solomon, A., 57 Tang, Y., 78, 80, 81, 83, 88, 106
Song, L., 78, 96 Tanner, C. M., 106
Sonne, S., 162, 169 Tapanainen, J., 24, 58
Southam, A. M., 30, 62 Tate, B. A., 36, 61
Spano, M. S., 44, 66 Tatemoto, K., 37, 70
Speaker, B., 69 Tavtigian, S., 19
Spencer, A., 51, 62 Taylor, P. J., 151, 166
Spima, P., 87, 105 Teilhac, J. R., 84, 101
Stacey, P., 82, 96 Tepper, M., 77, 107, 139, 144
Stancampiano, R., 90, 102 Terzian, H., 28, 70
Steers, W. D., 75, 79, 81, 84, 85, 96, 105 Tetel, M. J., 83, 106, 137, 144
Stefan, H., 114, 142 Thavundayil, J. X., 87, 100
Stein, D. J., 160, 169 Thede, L. L., 46, 59
Stein, E., 17, 20 Theodosis, D. T., 89, 106
Stein, E. A., 138, 144 Thibaut, F., 162, 169
Steinbusch, H., 83, 105, 156, 169 Thiessen, B., 106
Steinman, J. L., 110, 141, 144 Thomas, J. J., 28, 53, 66
Stellflug, J. N., 28, 68 Thomas, P. J., 65
Stenvert, L. S., 69 Thompson, J. T., 86, 93, 103, 107
Stock, S., 71 Thor, K. B., 84, 106
Stoller, R. J., 155, 169 Thornton, L M., 13, 19
Stormshak, F., 28, 68 Tiihonen, J., 137, 144
Strecker, R. E., 36, 61 Tilders, F. J. H., 70
Stromberg, P., 45, 61 Timmermann, L., 138, 144
Stuart, C. A., 66 Toniolo, M. V., 144
Stumpf, W. E., 82, 104 Tranel, D., 150, 165
Sturla, E., 25, 63 Trapp, B. D., 104
AUTHOR INDEX 191

Travers, S. P., 124, 144 Van Trotsenburg, M., 63
Treacher, D. F., 45, 64 Vares, T., 177, 178
Trivedi, S., 18, 57 Varga, M., 140
Truitt, W. A., 19, 106 Vargiu, L., 86, 89, 92, 97
Trujillo, R, 101 Veening, J. G., 83, 95, 106, 137, 144
Tseng, L. F., 96 Veldhuis, J. D., 22, 60
Tsukamoto, T., 90, 104 Verebey, K., 157, 169
Tucker Halpern, C, 22, 71 Verge", D., 92, 164
Turan, M., 23, 46, 71 Veridiano, N. P., 60, 66
Turkenburg, J. L., 36, 71 Vermeulen, A., 38, 72
Turnbull, A. C., 45, 66 Vernet, D., 90, 97
Turner, W. J., 71 Veronneau-Longueville, F., 82, 88, 106
Twitchell, G., 151, 167 Vertes, R. P., 80, 101
Tzschentke, T., 27, 68 Vihko, R., 24, 58
Viinamaki, O., 68
Vila, J. M., 69
Uberos-Fernandez, J., 67 Vilain, E., 26, 60
Udry, J. R., 22, 24, 71 Visser, T. J., 37, 61
Uematsu, Y., 69 Vodusek, D. B., 79, 107
Ugolini, O., 78, 100, 106 Volavka,]., 157, 169
Uitti, R. J., 87, 106 Volpicelli, J. R., 162, 169
Ulisse, S., 96 Voogt, J. L, 87, 107, 108
Unmehopa, U. A., 37, 64, 65 Vortmeyer, A., 71
Utsunomiya, H., 42, 70
Uvnas-Moberg, K., 44, 45, 71
Wagner, C. K., 75, 82, 88, 107
Wagner, G., 76, 92
Vainio, P., 144 Wakerley, J. B., 122, 138, 141
Valanis, B. G., 176, 178 Waldinger, M. D., 84, 85, 107
Valdueza, J. M., 29, 71 Walinder, J., 46, 65
Vallano, M. L., 90, 101, 157, 167 Walker, A. E., 151, 165
Valtschanoff, J. G., 91, 106 Walker, P. A., 66
Van, F. H., 66 Wallach, S. J. R., 16, 20
Van Bockstaele, E. J., 81, 106 Wallen, K., 138, 142
van Delft, A. M., 84, 93 Walsh, M. L., 29, 57
Van den Hurk, R., 53, 71 Walsh, P. C., 76, 107
Van de Poll, N. E, 36, 60, 71 Walter, A., 48, 72
Vanderah, T. W., 107 Walter, B., 28, 60
Van der Beek, E. M., 53, 71 Waltzer, R., 80, 101
Van der Donk, H. A., 53, 71 Wang, D. S., 141
van der Graaf, F. H. C. E., 142 Wang, Z., 43, 72
van der Kolk, B. A., 154, 155, 158-160, Warburton, V. L, 44, 59, 116, 141
165, 169 Ward, O. B., 26, 72
Van der Ploeg, L. H., 27, 71, 78, 89, 106 Ward, R. P., 85, 103
Van der Velde, E. A., 71 Ware, J. C., 104
Van Dis, H., 82, 106 Warner, R. K., 86, 99, 107
Van Eerdenburg, F J. C. M., 24, 71 Watabe, T., 26, 72
van Heerikhuizen, H., 84, 97 Watanabe, T., 69
Van Kemper, G. M. J., 71 Wayner, M. J., 143
Van Lorden, L., 71 Webb, A., 66
Van Ophemert, J., 54, 57 Weiller, C., 141
192 AUTHOR INDEX

Weinberg, M. S., 15, 18, 176, 178 Wisniewski, A. B., 23, 25, 72
Weinberg.R.J.,91, 106 Wisselink, P. G., 161, 166
Weisaeth, L, 160, 169 Wu, S. Y., 96
Weiss,}., 23, 46, 56
Weiss, R. A., 61
Wenkstern, D., 137, 144 Xu, J. Q., 141
Wersinger, S. R., 137, 145
Wertz, J. M., 84, 104
Wesensten, N. J., 140 Yahr, P., 27, 72
Wessels, H., 89, 90, 107 Yamaguchi, H., 94
Wessler, G., 96 Yamamoto, D., 16, 20
Westlin, L., 45, 71 Yamane, M., 81, 97
Weyl, N., 51, 72 Yamanouchi, K., 83, 100
Wheeler, M. J., 45, 64 Yanagimoto, M., 63, 82, 107
Whipple, B., 77, 100, 107, 109-116, 119, Yang, S. P., 87, 107, 108
137-139, 141-145 Yehuda, R, 154, 158, 169
Whipple, C, 114, 115, 141 Yells, D. P., 80, 83, 107, 108
Whitam, F. L, 12, 20 Young, L. J., 43, 72
Whitlock, E., 178 Young, S. E., 46, 59
Wiegant, V. M., 53, 71 Young, W. S., IIIL, 68
Wiersinga, W. M., 37, 61
Wikberg, J. E., 89, 107
Wilcox, C. S., 161, 166 Zaborszky, L., 142
Wildt, L, 123, 145 Zarefoss, S., 142
Willerman, L, 51, 57 Zderic, S. A., 23, 48, 72
Williams, D. M., 57 Zenchak, J. J., 16, 20
Williams, S., 78, 103 Zenut, M., 86, 95
Williams, S. J., 103 Zhang, L., 97
Wilson, C., 81, 92 Zhou, J. N., 31, 35, 49, 50, 53-55, 65,
Wilson, D. A., 104 70,72
Wilson, J. D., 23, 25, 63, 72 Zimmerman, I., 60
Winblad, B., 33, 62 Zorgniotti, A. W., 88, 107, 108
Winslow, J. T., 144 Zucker, K. J., 23, 46-48, 50, 51, 58, 72,
Winslow, W., 153, 168 73
AUTHOR INDEX 193

SUBJECT INDEX
A5 catecholaminergic cell group, 81 Anterior cingulate cortex, 138

Abuse, CSB and, 152, 154, 155 Anterior commissure, 30-32, 51, 134
ACTH (adrenocorticotropin), 89 Anterior hypothalamus
Activating effects of sex hormones, 55 during arousal, 121-123
Adoptive sibling studies, 11 sex differences in, 31
Adrenal, 24 Antiandrogen treatment, 153-154, 162
Adrenocorticotropin (ACTH), 89 Anticonvulsants, prenatal exposure to,
Age-related differences 26
in INAH-2, 41 Antidepressants, 85, 160-162, 173
in SDN-POA cell number, 33 Anxiety, 153
in SON, 42, 43 Apomorphine, 85-87
Aging, sex difference in pattern of, 38-39 Aromatase, 22
Agyei, Y., 11-12 Aromatization theory, 21-22, 24, 25
Alcohol Australian twin registry study, 12
prenatal exposure to, 26 Autoerotic asphyxia, 161
and testosterone, 153 Autonomic function
Alpha-1 adrenoceptor antagonists, 87, 88 and CSB, 154-155
Alpha-2 adrenoceptor agonists, 87, 88 and nitric oxide, 91
Alpha-melanocyte-stimulating hormones Axons, 80
(alpha-MSH), 89
Amphetamine, 87, 157
Amygdala, 83, 154 Bailey, J. M, 11-14
aromatase in, 22 Bancroft, John, 153
BST connections with, 49 Barrington's nucleus, 81
and CSB, 149 Basal ganglia
and erectile dysfunction, 27 during arousal, 121, 122
orgasm and activation of, 127, 132, orgasm and activation of, 137
133, 137, 138 Bed nucleus of the stria terminalis
and sexual orientation, 28 (BST)
Analgesia, self-stimulation-induced, 113, dspm area of, 31, 49
114,116 and erectile functions, 27
Anal sex, 91 estrogen/androgen receptors in, 48
Androgen insensitivity syndrome, 25 lesions of, in rats, 28
Androgen receptors, 25 orgasm and activation of, 127, 133,
in BST, 48, 49 137
in hypothalamus, 82, 174 principal sectors in, 49
in midbrain, 81 in rats, 48-49
in SDN-POA, 37 sexual-behavior regions of, 173
sex differences in, 41, 173 and sexual differentiation of brain,
Androgens 24
and male gender identity, 48 and transsexuality, 45-50
and sexual differentiation of brain, in transsexuals, 173
22, 24, 25 Bell, A. P., 14
Androphilic transsexuality, 172 Benishay, D. S., 14
195
Bisexuality hypothalamus, 82-83
and diethylstilboestrol exposure of interneurons, 78-79
mother, 22 medulla, 80
in females, 50 midbrain, 81
in lesbians vs. gay men, 15 motor mechanisms, 76-77
in sibling studies, 14 pons, 81
Bladder activity inhibition, 79 sensory mechanisms, 77-78
Bladder control, 81 spinal reflexes, 79-80
Brain Central nucleus of BST (BSTc), 31, 35,
regions activated during orgasm, 49-50
127-138 Cerebellum, 137, 138
sexual-behavior regions of, 173 Cervical self-stimulation, spinal cord
sexual differentiation of. See Sexual injury and. See Brain-imaging
differentiation of brain studies
weight of, 24 Cervix, 76
Brain-imaging studies, 109-140 C-fos gene, 78
animal study evidence for C-fos method, 175-176
hypothesis, 114-115 Child abuse, CSB and, 154, 155
brain regions activated during Child molesters, 153
orgasm, 137-138 l-(3-Chlorophenyl)-piperazine (m-CPP),
fMRI method in, 123-136 84
genital sensory nerves, functions of, Chromosomal abnormalities, 46
110 Cingulate cortex, 127, 132, 133, 137,
implications for practitioners, 138
139-140 Climax, 84
methodology, 112-113 Clitoral priapism, 85
pain measurement in, 111-112 Clitoris, 76, 79
PET method in, 115-123 Cloacal exstrophy, 47
tactile thresholds in, 111-112 Clonidine, 87
Vagus nerves, 111-112, 135, 137 Cocaine, 87, 157
Brainstem, sexual-behavior regions of, Cognition, sex differences in, 29
173 Cognitive-genital dissociation, 139. See
BST. See Bed nucleus of the stria also Spinal cord injury
terminalis Commissura anterior, 51
BSTc. See Central nucleus of BST Complete androgen insensitivity
BST-dspm. See Darkly staining syndrome, 25
posteromedial of BST Compulsive sexual behavior (CSB),
Bulbocavernosus reflex, 79 147-178
Bulbospongiosus muscles, 79 and autonomic reactivity/
neurotransmitter dysregulation,
154-156
Carbamazapine, 152, 161 and dopamine dysregulation, 157
Caudate, 138 and frontal lobe abnormalities, 150
Cavernous nerve, 76, 79, 80, 84 neuroanatomical abnormalities with,
Central gray matter 149-152
and interneurons, 78, 79 neurophystochemical abnormalities
orgasm and activation of, 137 with, 152-160
sensory mechanisms of, 77, 78 nonparaphilic, 148
Central nervous system, sexual function and norepinephrine dysregulation,
control in, 75-83 155, 156
forebrain, 83 and opioids, 157-160
196 SUBJECT INDEX

paraphilic, 148-149 Ejaculation
pharmacological treatment of, and dopamine, 85
160-163 and opiates, 157
and serotonin dysregulation, and serotonin, 84, 85
156-157 and spinal reflex, 79
and temporal lobe abnormalities, and SSRIs, 156
150-152 Emotional abuse, CSB and, 152
and testosterone abnormalities, Endocrine system. See
152-154 Hypothalamus
Computer tomography imaging (CT), Endogenous opiates, 157
150 Endorphins, 157-159
Concordant twin pairs, 10, 12 Enkephalins, 157
Congenital adrenal hyperplasia, 46, 50 Ephebophilia, 29
Copulatory behavior Erectile functions
and dopamine, 85, 86 and biologically active peptides,
mPOA and, 27-28, 34, 36 89-90
and nitric oxide, 90 and brain regions, 173
and noradrenaline, 87-88 and dopamine, 86, 87
and opiates, 90 and hypothalamus/amygdala, 27
and serotonin, 84 and nitric oxide, 90
Courtless gene (fruit flies), 16 and noradrenaline, 88
CSB. See Compulsive sexual behavior and opiates, 90
CT (computer tomography imaging), 150 and oxytocin, 88-89
CYP19 gene, 50 and preoptic area, 34, 36
Cyproterone acetate, 162 and serotonin, 84
and spinal reflex, 79
and supraoptic/paraventricular
Dl receptors, 85-86 nucleus, 43-44
D2 receptors, 84-86 Erotomania, 147
Darkly staining posteromedial of BST Estrogen receptors
(BST-dspm), 30, 31, 49 in amygdala, 28
Defecation, 81 in BST, 48
DES. See Diethylstilboestrol in SDN-POA, 37-38
Diagnosis of sexual orientations, 176 sensory mechanisms of, 77
Diagnostic and Statistical Manual of Mental sex differences in, 42
Disorders (DSM1V-TR), 148 Estrogens, sexual differentiation of brain
Diamond, M., 12 and, 22, 24-25
Diencephalic dopaminergic cells, 85 Ethical issues with genetic technologies,
Diethylstilboestrol (DES), 50 17
Discordant twin pairs, 10, 12 Excitatory pathways, 75-76, 86
Dopamine Ex copula erections, 80
and CSB, 155, 157 Exhibitionism, 29
and nitric oxide, 90
in PVN, erection function and, 44
and sexual function, 84-87 Familial studies of sexual orientation,
Dorsal horn, 77, 78 13-14
Drosophila, 16, 172 Fear response, 154, 155
Drugs, prenatal exposure to, 26 Females
DSM4V-TR (Diagnostic and Statistical brain regions activated during
Manual of Mental Disorders), 148 orgasm in, 127-138
Dunne, M. P., 12 clitoral priapism in, 85
SUBJECT INDEX 197

Females, continued and prenatal nicotine exposure, 51
complete androgen insensitivity SCN differences in, 51-53
syndrome in, 25 SDN-POA in, 39
congenital adrenal hyperplasia in, 46 sibling studies of, 14
copulatory behavior in, 27-28 subtypes of, 15
and dopamine, 86-87 twin study concordance rates for, 16
motoneurons in, 77 Xq29 gene in, 14
and noradrenaline, 87-88 Gender identity. See also Transsexuality
and oxytocin, 88, 89 and brain-sex hormone interaction,
oxytocin levels in, 45 48-49
sensory mechanisms in, 77 BST role in, 173
and sex differences in hypothalamus. factors influencing, 23
See Hypothalamus genome scan for, 15
and sex differences in SDN-POA, genomewide scan, 15
172 in females, 25
sexual differentiation of brain in, 22, and gender reassignment, 47-48
24-25 in males, 25
with spinal cord injury, sexual Gender imprinting, 47
response in. See Brain-imaging Genetics of sexual orientation, 9-18, 172
studies animal model research on, 16-17
spinal reflexes in, 79-80 ethical issues related to, 17
vasopressin levels in, 45 gender differences in, 15-16
Ferguson reflex, 138 non-twin familial studies, 13-14
Ferrets, 36 and single-gene hypothesis, 14
Fetishes, 150 twin and adoption studies, 10-13
Fight-or-flight responses, 149 and types of homosexualities, 15
fMRI. See Functional magnetic resonance Genital sensory pathways. See also
imaging Brain-imaging studies
Forebrain, 83 division of labor among nerves, 110
Fornix, 30 and spinal cord injury, 109, 174
Fos gene product, 78, 83 via Vagus nerves, 111-112, 135, 137
Frontal cortex, 137 Genital sensory stimulation, 82, 89
Frontal lobe "Genitosensory Vagus" hypothesis,
and CSB, 149, 150 113-115
sexual-behavior regions of, 173 Gerbils, 53
and sexuality, 173 Oilman, S. E., 13
Fruitless gene (fruit flies), 16 Golgi apparatus
Fuguelike state, 151, 157 age-related differences in, 43
Functional magnetic resonance imaging sex differences in, 42, 43
(fMRI), 115, 116, 123-136 Gonadotropins, 29
Grafenberg spot, 112
Gray matter, 76-79
GABA (gamma-amino butyric acid), 37 orgasm and activation of central,
Galanin, 36, 37, 49 137
Gamma-amino butyric acid (GABA), 37 oxytocin in, 88
Gay men periaqueductal, 81
genetic influences on lesbians vs., 15 Gynephilic transsexuality, 172
hypothalamus differentiation in, 39
linkage studies of, 14
and maternal stress, 51 Hamartoma, 29
pedigree studies of, 14 Hermaphroditism, 48
198 SUBJECT INDEX

Heterosexuality sexually dimorphic nucleus of
and androgen action on brain, 25 preoptic area, 33-36
factors influencing, 23 sexually dimorphic structures in,
and lesions in hypothalamus, 29 30-33
Hippocampus structural differences in, 39, 41
aromatase in, 22 supraoptic and paraventricular nu-
and CSB, 149, 155, 156 cleus, 42-45
orgasm and activation of, 135-138 ventromedial nucleus of, 29
Homosexualities
factors influencing, 23
gender differences in, 15-16 Identity, sexual, 10, 172
and hypothalmic structures, 50-54 Immune system, 15
in lesbians vs. gay men, 15 INAH. See Interstitial nucleus of anterior
and lesions of hypothalamus/ hypothalamus
temporal lobe, 28, 29 Incertohypothalamic pathway, 85
in men. See Gay men Inescapable shock, 155
in sibling studies, 14 Infundibular nucleus, 31
twin studies of, 10-11 Infundibulum, 30
types of, 15 Insula, 133
in women. See Lesbians Insular cortex, 127, 132, 133, 137, 138
Hormonal cues, 82 Interdisciplinary collaborations, 176-
Hormone-independent sexual 177
differentiation, 26 Intermediate nucleus, 37
Hormones. See Sex hormones Intermediolateral cell column, 78
H-Y antigen, 15 Interneurons, 78-79, 81
8-Hydroxy-2-(di-n-propylamino) tetralin Interstitial nucleus of anterior
(8-OH DPAT), 84 hypothalamus (INAH), 30, 31,
Hypersexual behavior, 149-151 37-39, 41, 51, 54
Hypersexuality, 29, 147 Ischiocavemosus muscles, 79
Hypogastric nerves, 79, 110
Hypogonadism, 29
Hypothalamus, 27-55, 82-83 James I, King of England, 51
androgen receptors in, 174
anterior, 31, 121-123
aromatase in, 22 Kallman, F. J., 11
during arousal, 121-123 Kendler, K. S, 13
BST and transsexuality, 45-50 Kessler, R. C., 13
and CSB, 157 King, M. N., 12
development/sexual differentiation of Kinsey, Alfred, 9-10
SDN-POA, 38-40 Kinsey rating scale, 10, 15
homology of human to rat Klviver-Bucy syndrome, 28, 151
SDN-POA, 36-38
and homosexuality, 50-54
and noradrenaline, 87 L3 spinal segment, 79
orgasm and activation of, 127, 132, L4 spinal segment, 79
133, 137-138 L6-S1 spinal cord, 88
sex hormone receptor distribution Lactation, oxytocin and, 44
differences, 41—42 Lateral ventricle, 30
sexual-behavior regions of, 173 Lesbians
sexual differentiation of, 24 and congenital adrenal hyperplasia,
and sexual function control, 82-83 50
SUBJECT INDEX 199

Lesbians, continued and sex differences in SDN-POA, 172
and diethylstilboestrol exposure of sexual differentiation of brain in, 22,
mother, 22 24-26
genetic influences on gay men vs., 15 spinal reflexes in, 79-80
genetic studies of, 11-12 Martin, J., 12
and prenatal nicotine exposure, 51 Mary, Queen of Scots, 51
and sex hormones, 50-51 Maternal stress, 51
sibling studies of, 13-14 MC4 receptors, 89
subtypes of, 15 M-CCP, 85
twin study concordance rates for, 16 McDonald, E., 12
undertheorization concerning, 16 MC receptors. See Melanocortin
Leuprolide acetate, 162 receptors
LHRH. See Luteinizing hormone- Measurement
releasing hormone accuracy in, 176
Limbic system advanced technologies for, 175
and CSB, 149 of pain, 111-112
and opioids, 157 of sexual orientation, 9-10
orgasm and activation of, 137, 173 of testosterone, 153
sex differences in, 27-28 Medial amygdala, 27
Linkage analysis, 14 Medial-basal hypothalamic dopamine
Lithium carbonate, 161 neurons, 27
Locus ceruleus, 81, 87 Medial mamillary nucleus (MMN),
Lordosis response, 45 41-42
Lower brainstem, 137 Medial preoptic area (MPOA)
Lumbosacral spinal cord, 77, 78, 80, 85, 88 and copulatory behavior, 27, 34, 36
Luprolide acetate, 162 and dopamine, 85-87
Luteinizing hormone-releasing hormone and hypothalamus, 82
(LHRH), 49, 53, 157, 162 and nitric oxide, 90-91
Medroxyprogesterone acetate, 162
Medulla, 80
MacArthur Foundation, 13 Melanocortin agonists, 27
Magnetic resonance imaging (MRI), 150. Melanocortin (MC) receptors, 78, 89-90
See also Functional magnetic Melanotan II, 89-90
resonance imaging Mesencephalic reticular formation, 137
Male pseudohermaphroditism, 47 5-Methoxytryptophol, 54
Males Mice, 26
brain regions activated during Midbrain, 81
orgasm in, 137-138 Midbrain reticular formation, 120-122
copulatory behavior in, 27-28 Midlife Development in the United
and dopamine, 86, 87 States (MIDUS) survey, 13
erectile functions in, 27 MIDUS survey. See Midlife Development
gender identity in, 25 in the United States survey
heterosexuality development in, 25 Minnesota Twin Registry study, 12
and hypothalamus, 82 MMN. See Medial mamillary nucleus
motoneurons in, 77 Monkeys
and noradrenaline, 87, 88 erection functions in, 27, 29
and oxytocin, 88-89 hypothalmic structures in, 54
prenatal alcohol exposure in, 26 PVN and erection in, 43
priapism in, 85 SDN-POA in, 36-37
and sex differences in hypothalamus. Mood stabilizers, 161
See Hypothalamus Motor mechanisms, 76-77
200 SUBJECT INDEX

mPOA. See Medial preoptic area NPG1 (nucleus paragigantocellularis), 80
MRI (magnetic resonance imaging), 150 N-trifluoromethylphenylpiperazine
MTII, 27 (TFMPP), 84
NTS. See Nucleus of the solitary tract
Nucleus accumbens, orgasm and
Naloxon, 44 activation of, 133, 137, 138
Naloxone, 90 Nucleus of the solitary tract (NTS), 115,
Naltrexone, 90, 162-163 116
National Health and Social Life Survey, fMRI imaging of, 123-136
10 orgasm and activation of, 137
Neale, M. C., 11-12 PET imaging of, 116-120
Nefazadone, 161 Nucleus paragigantocellularis (nPGi), 80
Neocortex, 137 Nymphomania, 147
Nerves, genital sensory, 110, 174
Neuroanatomical abnormalities, 149-152
Neurological diseases, 29 Obesity, 89
Neurological pharmacological agents, Obsessive-compulsive disorder, 159
83-91 1A receptor subtype, 84, 85
adrenocorticotropin, 89-90 IB receptor subtype, 84
biologically active peptides, 89-90 Opiates, 90, 157
dopamine, 85-87 Opioids, 157-160
nitric oxide, 90-91 Optic chiasm, 30, 31
noradrenaline, 87-88 Optic tract, 30
opiates, 90 Organum vasculosum lamina terminalis,
oxytocin, 88-89 31
serotonin, 83-85 Orgasm, 85
Neurophysiochemical abnormalities, brain regions activated during,
152-160 127-138
autonomic reactivity/ and oxytocin levels, 122-123
neurotransmitter dysregulation, and SSRIs, 156
154-156 Orgasms
norepinephrine dysregulation, 155, and oxytocin levels, 44-45
156 in women with spinal cord injury.
opioids, 157-160 See Brain-imaging studies
serotonin/dopamine dysregulation, Osteopenia, 162
156-157 Oxytocin, 82, 86, 88-89
testosterone, 152-154 and human maternal behavior, 44
Neurotransmitter dysregulation, 158-159 and nitric oxide, 90, 91
Neurotransmitters. See also Serotonin, orgasm and levels of, 122-123
Dopamine orgasm and secretion of, 138, 174
CSB and dysregulation of, 155, 156 in PVN and SON, 43-44
metabolism of, 26 sex differences in, 43-45
Neurotrophin receptors, 43 Oxytocinergic neurons (of PVN), 34, 36
Nitric oxide, 76, 90-91 Oxytocin receptor, 45
Nitric oxide synthase (NOS), 90
NO, 76, 90-91
Nocturnal tumescence, 85 P75 neurotrophin receptor (p75NTR), 27
Nonparaphilic CSB, 148 Pain
Noradrenaline, 87-88 brain regions activated by, 138
Norepinephrine, 155-156 threshold of, in brain-imaging
NOS (nitric oxide synthase), 90 studies, 111-113
SUBJECT INDEX 201

Pair bonding, 16, 89 Pheromones, 43
Paleomammalian cortex, 149 Phosphodiesterase Type 5 inhibitors, 88
Paraphilic CSB, 148-149 Physical abuse, CSB and, 152
and brain abnormalities, 150 Phytoestrogens, 51
and temporal lobe abnormalities, Pillard, R. C, 11-12
150-151 Pineal region tumors, 29
Parasympathetic preganglionic neurons, Pituitary, 42
76,81 Plasma prolactin concentrations, 27
Paraventricular nucleus (PVN), 30, 31 Pleasure, brain regions activated by, 138
activation of, in women with spinal POA. See Preoptic area
cord injury, 116 Polygenic traits, 14
during arousal, 121-123 Polysynaptic reflex, 79
and dopamine, 85, 86 Pons (pontine micturition center), 22,
and erectile functions, 27, 34, 36, 81
173 "Poppers," 91
and hypothalamus, 82-83 Positron emission tomography (PET),
and nitric oxide, 90 115-123, 150
orgasm and activation of, 127, 134, Postganglionic neurons, 76
137, 138, 174 Posttraumatic stress disorder (PTSD),
and orgasm in women, 173 154-156, 158
and oxytocin, 88-89 Prazosin, 87
sex differences in, 42-45 Precocious puberty, 29
Parietal cortex, 137 Preganglionic neurons, 76-77
Parkinsonism, 86, 157 Pregnancy, induction of, 77
Parturition, 81 Preoptic area (POA). See oho Sexually
Pedigree analysis, 14 dimorphic nucleus of preoptic
Pedophilia area
and brain injury, 149, 150 medial, copulatory behavior and, 27
and lesions of hypothalamus/ sex differences in, 31
temporal lobe, 28, 29 and sexual orientation, 28
and temporal lobe abnormalities, Priapism, 85
150-152 Pro-opiomelanocortin, 89
Pelvic function, 91 Prostate, 76
Pelvic ganglion, 76 Proust, Marcel, 51
Pelvic innervation, 76-78 Pseudohermaphroditism, 47
Pelvic interneurons, 78 Pseudopregnancy, 77
Pelvic nerves, 110 Pseudorabies virus, 78, 88
Penile ablation, 47 Psychiatric diseases, 29
Penis, 76, 78 PT 141, 27, 90
Peptide systems, 158 PTSD. See Posttraumatic stress disorder
Periaqueductal gray, 81 Pudendal nerve, 77-79, 81
Period gene (fruit flies), 16 Pudendal nerves, 110
PET. See Positron emission tomography Putamen, 137
Pharmacological treatment (of CSB), PVN. See Paraventricular nucleus
160-163 Pyriform cortex, 83
Pharmacology of sexual function. See
Neurological pharmacological
agents Rapists, 153
Phentolamine, 88 Rats
Phenylpiperazine reuptake inhibitor BST in, 48-49
effects, 161 erectile functions in, 27
202 SUBJECT INDEX

female, genital sensory nerves in, Serotonin, 83-85
110 and CSB, 155
female, orgasm in, 137 CSB and dysregulation of, 156-
neurons of NTS in, 115 157
oxytocin and sexual behaviors in, and medulla/pons, 80
44, 45 Serotonin 5 HT2 receptor subtype, 161
partner preference and BST lesions 7-point scale of sexual orientation, 10
in, 28 Sex hormone receptors, 41-42. See oho
preoptic area in, 36 specific hormone receptors
PVN lesions in, 43 Sex hormones. See also specific hormones
SCN differences in, 53, 54 activating effects of, 55
SDN-POA in humans vs., 36-38 decrease in SDN-POA cells and,
sex differences in SDN-POA in, 38
172 interaction of developing brain and,
sexual behavior and exposure to 39
drugs, 26 interaction of oxytocin and, 45
SON of, 43 metabolism of, 26
Vagus nerve pathway in, 114-115 puberty and levels of, 172
vasopressin and copulatory behavior and sexual differentiation of brain,
in, 45 22-26
Reflexes, spinal, 79-80, 173 and sexual orientation, 50-51
Registry studies of sexual orientation, Sexual addiction, 147
12-13 Sexual behavior
Relationship issues, 177 compulsive. See Compulsive sexual
Reproduction, SCN role in, 53, 54 behavior
Research technology, advances in, and exposure to drugs, 26
175-176 and galanin in medial preoptic
Robinson, Gene, 9 nucleus, 37
Rodents, 24, 25. See also Mice; Rats hypothalamus and adjoining
RSD 992, 84 structures, role of, 28-29
relationship issues in, 177
SCN role in, 53, 54
Sacral parasympathetic nucleus, 77, 88 sexual identity vs., 10, 172
Satyriasis, 147 spinal cord role in, 173-174
SCN. See Suprachiasmatic nucleus Sexual desire, SSRIs and, 156
SON. See Sexually dimorphic nucleus Sexual differentiation of brain, 21-29.
SDN-POA. See Sexually dimorphic See also Hypothalamus
nucleus of preoptic area aromatization theory, 21-22, 24
Seizures, 151 direct effect of testosterone in,
Selective serotonin reuptake inhibitors 24-25
(SSRIs), 160-162, 173 factors influencing, 23
and medulla/pons, 80 and hormone/neurotransmitter
and serotonin, 84, 85, 156-157 metabolism, 26
Selegiline, 86 in humans, 28-29
Self-medication, 157 in hypothalamus and limbic
Sensory cues, 82 structures, 27-28
Sensory mechanisms, 77-78 Sexual disenfranchisement (spinal cord
Septum, 149 injury), 139
lesions in, 27 Sexual identity, 10, 172
orgasm and activation of, 133 Sexuality, complexity of, 172
and sexual behavior, 28-29 Sexually dimorphic nucleus (SDN), 35
SUBJECT INDEX 203

Sexually dimorphic nucleus of preoptic SON. See Supraoptic nucleus
area (SDN-POA), 30, 31, 33-36, Sphincter reflexes, 81
173 Spinal cord, 173-174
age-related changes in cell number Spinal cord injury, 109-145
of, 33 ejaculation in men with, 79
and copulatory behavior, 27 orgasm in women with, 79
development/sexual differentiation sexual response in women with.
of, 34, 38-40 See Brain-imaging studies
in humans vs. rats, 36-38 trajectory of adjustment to,
sex differences in, 32, 172 139
sexual differentiation of, 30 Spinal innervation, 76-83
Sexual motivation forebrain, 83
and dopamine, 86-87 hypothalamus, 82-83
and forebrain, 83 interneurons, 78-79
and hypothalamus, 82 medulla and pons, 80-81
and noradrenaline, 87 midbrain, 81
Sexual neutrality at birth, 47 motor mechanisms, 76-77
Sexual orientation sensory mechanisms, 77-78
amydgala, role in, 28 spinal reflexes, 79-80
and androgen action on brain, 25 Spinal reflexes, 79-80, 173
in animals, 16-17 SRY gene, 26, 174
brain injury and changes in, 151 SSRIs. See Selective serotonin
diagnosis of, 176 reuptake inhibitors
factors influencing, 23 Stress, 158-159
following sex change, 172 and opiates, 157-158
genetic factors in and influences on, and PTSD, 154
50. See Genetics of sexual and testosterone, 153
orientation Striated perineal muscles, 77, 79-
and hypothalmic structure 80
differences, 51-53 Stroke victims, 151
and interaction of developing brain Subceruleus, 87
and sex hormones, 39 Substantia innominata, 49
measurement of, 9-10 Suprachiasmatic nucleus (SCN), 30,
postnatal social factors in, 51 31,39
prenatal factors in, 50-51 and homosexuality, 51-54
SDN-POA, role of, 36 innervated by VIP, 35
and sex hormones during sex differences in, 31
development, 50-51 and sexual orientation, 51
temporal lobe, role of, 28 Supraoptic nucleus (SON), 30, 31,
Sexual rediscovery (spinal cord injury), 33
139 age-related differences in, 43
Sexual reflexes, spinal, 173 oxytocin innervation in, 89
Sheep, 16, 28 sex differences in, 42-45
Sibling studies of sexual orientation, Sympathetic preganglionic neurons,
10-14 76,81
Sildenafil, 88
Single-gene hypothesis, 14
Skin (of penis), 78 Tactile threshold (in brain-imaging
Social factors in sexual orientation, studies), 112, 113
50-51 Technologies, research, 175-176
204 SUBJECT INDEX

Temporal lobe, 150-152 Vagal pathway, 77-78
change in sexual behavior and Vaginal self-stimulation, spinal cord
damage to, 28 injury and. See Brain-imaging
and compulsive sexual behavior, studies
173 Vaginocervical stimulation, 83
sexual-behavior regions of, 173 Vagus nerves, 111-115, 135, 137,
Testicular steroidogenesis, 162 174. See also Brain-imaging
Testosterone, 24-25, 82 studies
and CSB, 152-154 Valproic acid, 161
formation of, 21 Van der Kolk, B. A., 155, 158-159
measurement of, 153 Vasodilatory innervation, 76
and sexual differentiation of brain, Vasopressin
22,24 and erectile function, 44
TFMPP (N-trifluoromethylphenyl- sex differences in, 42-45, 54
piperazine), 84 Ventral tegmental field of midbrain, 81
Thalamus, 22 Ventromedial nucleus of hypothalamus,
Third ventricle, 30, 31 29
Thornton, L. M., 13 Viagra, 88, 177
Transneuronal labeling techniques, 176 Viral tracing, 78, 80-83
Transsexuality Viruses, 78
and BST, 45-50, 173 Volatile nitrites, 91
factors influencing, 23
incidence of, 45-46
and prenatal exposure to Whitam, F. L., 12
anticonvulsants, 26 White matter, 76
subcategories of, 172
Trauma, 155, 156, 158-160, 163
Trazodone, 85 Xq28 gene, 14, 50
Twin studies, 10-13
2A receptor subtype, 84, 85
2C receptor subtype, 84, 85 Yohimbine, 87, 88
Urinary continence, 79 Zebra finches, genetic studies of, 16-17

Uterus, 77 ZFY gene, 26
SUBJECT INDEX 205

ABOUT THE EDITOR
Janet Shibley Hyde, PhD, is the Helen Thompson Woolley Professor of

Psychology and Women's Studies at the University of Wisconsin—Madison.
She earned her BA in mathematics from Oberlin College and her PhD in
psychology from the University of California, Berkeley. After an early re-
search career as a behavior geneticist, she focused her scholarly energies on
the areas of human sexuality and the psychology of women. The author of
more than 100 articles and chapters, she has conducted meta-analyses of
studies of psychological gender differences in areas such as self-esteem,
mathematics performance, and sexuality. Another line of her research has
been sexuality in marriage. She is the author of the undergraduate textbook,
Half the Human Experience: The Psychology of Women, now in its sixth
edition, and is coauthor, with John DeLamater, of Understanding Human
Sexuality, now in it's ninth edition. She has received awards for her research,
including the Heritage Award from the Society for the Psychology of Women
(American Psychological Association Division 35) and the Kinsey Award
from the Society for the Scientific Study of Sexuality.
207

Biological Substrates of Human Sexuality

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Biological Substrates of Human Sexuality

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Substrates^

edited by Janet Shibley Hyde

AMERICAN PSYCHOLOGICAL ASSOCIATION

To order In the U.K., Europe, Africa, and the Middle

Typeset in Goudy by World Composition Services, Inc., Sterling, VA

Printer: Victor Graphics, Inc., Baltimore, MD

Library of Congress Cataloging-in-Publication Data

British Library Cataloguing-in-Publication Data

Printed in the United States of America

Chapter 1. Introduction: The Role of Modern Neuroscience in

Eli Coleman, University of Minnesota Medical School, Minneapolis

This volume began with a conference on the biological substrates of

The past decade has witnessed an explosion of neuroscience research

4 JANET SHIBLEY HYDE

JANET SHIBLEY HYDE

Adkins-Regan, E. (2002). Development of sexual partner preference in the zebra

EVIDENCE FROM TWIN AND ADOPTION STUDIES

Behavior geneticists who study humans cannot perform the experimen-

10 JANET SHIBLEY HYDE

THE GENETICS OF SEXUAL ORIENTATION 11

]2 JANET SHIBLEY HYDE

TWIN STUDIES: THE EQUAL ENVIRONMENTS ASSUMPTION

In twin studies, differences between concordance rates for MZ versus

OTHER FAMILIAL STUDIES

Other behavior-genetic designs involve assessing resemblance for

THE GENETICS OF SEXUAL ORIENTATION 13

THE SINGLE-GENE HYPOTHESIS

Most behaviors that are genetically influenced, particularly those that

14 JANET SH1BLEY HYDE

DIFFERENCES BETWEEN GAY MEN AND LESBIANS

Several lines of evidence lead to the conclusion that lesbians differ

THE GENETICS OF SEXUAL ORIENTATION J5

RESEARCH WITH ANIMAL MODELS

Because genetic research on sexual orientation is so difficult with

16 JANET SHIBLEY HYDE

THE GENETICS OF SEXUAL ORIENTATION 17

Twin studies with humans provide evidence that homosexual orienta-

Adkins-Regan, E. (2002). Development of sexual partner preference in the zebra

18 JANET SHIBLEY HYDE

THE GENETICS OF SEXUAL ORIENTATION 19

20 JANET SHIBLEY HYDE

MECHANISM OF SEXUAL DIFFERENTIATION OF THE BRAIN:

Testosterone is formed in the fetal Leydig cells in the testicle from

Sexual Orientation (homosexuality, heterosexuality)

THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 23

Direct Effect of Testosterone

Although the process by.,which estrogens are derived from testosterone

THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 25

Sex differences in the hypothalamus and other limbic structures are

THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 27

A few studies have been presented in the medical literature that

SEX DIFFERENCES IN THE HYPOTHALAMUS

THE ROLE OF HYPOTHALAML/S AND ENDOCRINE SYSTEM 29

Figure 3.1. Topography of the sexually dimorphic structures in the human

The hypothalamus contains a number of structurally sexually dimorphic

THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 31

Sexually dimorphic nucleus

sexually dimorphic (Allen & Gorski, 1991). 5-hydroxyindoleacetic acid

Sexually Dimorphic Nucleus of the Preoptic Area

THE ROLE OF HYPOTHALAMUS AND ENDOCRINE SYSTEM 33

THE ROLE OF HYPOTHALAML7S AND ENDOCRINE SYSTEM 35

Homology to the Rat SDN-POA

The SDN-POA in the young adult human brain is twice as large in

THE ROLE OF HYPOTHALAML7S AND ENDOCRINE SYSTEM 37